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  • 1.
    Abraham-Nordling, Mirna
    et al.
    Karolinska institutet.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Nordling, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Model of the complex of Parathyroid hormone-2receptor and Tuberoinfundibular peptide of39 residues2010Ingår i: BMC Reseach Notes, ISSN 1756-0500, Vol. 3, nr 270Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.

    Findings

    In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation.

    Conclusions

    A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

  • 2.
    Al-Absi, Thabit
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Efficient Characterization of Short Anelloviruses Fragments Found in Metagenomic Samples2012Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Some viral metagenomic serum samples contain a huge amount of Anellovirus, which is a genetically diverse family with a few conserved regions making it hard to efficiently characterize. Multiple sequence alignment of the Anelloviruses found in the sample must be constructed to get a clear picture of Anellovirus diversity and to identify stable regions. Using available multiple sequence alignment software directly on these fragments results in an MSA of a very poor quality due to their diversity, misaligned regions and low-quality regions present in the sequence.

    An efficient MSA must be constructed in order to characterize these Anellovirus present in the samples. Pairwise alignment is used to align one fragment to the database sequences at a time. The fragments are then aligned to the database sequences using the start and end position from the pairwise alignment results. The algorithm will also exclude non-aligned portions of the fragments, as these are very hard to handle properly and are often products of misassembly or chimeric sequenced fragments. Other tools to aid further analysis were developed, such as finding a non-overlapping window that contains the most fragments, find consensus of the alignment and extract any regions from the MSA for further analysis.

    An MSA was constructed with a high percent of correctly aligned bases compared to an MSA constructed using MSA softwares. The minimal number of genomes found in the sampled sequence was found as well as a distribution of the fragments along the database sequence. Moreover, highly conserved region and the window containing most fragments were extracted from the MSA and phylogenetic trees were constructed for these regions. 

  • 3.
    Alexsson, Andrei
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Unsupervised hidden Markov model for automatic analysis of expressed sequence tags2011Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    This thesis provides an in-depth analyze of expressed sequence tags (EST) that represent pieces of eukaryotic mRNA by using unsupervised hidden Markov model (HMM). ESTs are short nucleotide sequences that are used primarily for rapid identificationof new genes with potential coding regions (CDS). ESTs are made by sequencing on double-stranded cDNA and the synthesizedESTs are stored in digital form, usually in FASTA format. Since sequencing is often randomized and that parts of mRNA contain non-coding regions, some ESTs will not represent CDS.It is desired to remove these unwanted ESTs if the purpose is to identifygenes associated with CDS. Application of stochastic HMM allow identification of region contents in a EST. Softwares like ESTScanuse HMM in which a training of the HMM is done by supervised learning with annotated data. However, because there are not always annotated data at hand this thesis focus on the ability to train an HMM with unsupervised learning on data containing ESTs, both with and without CDS. But the data used for training is not annotated, i.e. the regions that an EST consists of are unknown. In this thesis a new HMM is introduced where the parameters of the HMM are in focus so that they are reasonablyconsistent with biologically important regionsof an mRNA such as the Kozak sequence, poly(A)-signals and poly(A)-tails to guide the training and decoding correctly with ESTs to proper statesin the HMM. Transition probabilities in the HMMhas been adapted so that it represents the mean length and distribution of the different regions in mRNA. Testing of the HMM's specificity and sensitivityhave been performed via BLAST by blasting each EST and compare the BLAST results with the HMM prediction results.A regression analysis test shows that the length of ESTs used when training the HMM is significantly important, the longer the better. The final resultsshows that it is possible to train an HMM with unsupervised machine learning but to be comparable to supervised machine learning as ESTScan, further expansion of the HMM is necessary such as frame-shift correction of ESTs byimproving the HMM's ability to choose correctly positioned start codons or nucleotides. Usually the false positive results are because of incorrectly positioned start codons leadingto too short CDS lengths. Since no frame-shift correction is implemented, short predicted CDS lengths are not acceptable and is hence not counted as coding regionsduring prediction. However, when there is a lack of supervised models then unsupervised HMM is a potential replacement with stable performance and able to be adapted forany eukaryotic organism.

  • 4.
    Almgren, Malin
    et al.
    Karolinska Institutet.
    Nyengaard, Jens R
    Aarhus University.
    Persson, Bengt
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Lavebratt, Catharina
    Karolinska Institutet.
    Carbamazepine protects against neuronal hyperplasia and abnormal gene expression in the megencephaly mouse2008Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 32, s. 364-376Artikel i tidskrift (Refereegranskat)
  • 5.
    Almstedt, Karin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Lundqvist, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II2004Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 342, nr 2, s. 619-633Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.

  • 6.
    Anandapadmanaban, Madhanagopal
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Pilstål, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Andrésen, Cecilia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Trewhella, Jill
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. University of Sydney, Australia.
    Moche, Martin
    Karolinska Institute, Sweden.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Mutation-Induced Population Shift in the MexR Conformational Ensemble Disengages DNA Binding: A Novel Mechanism for MarR Family Derepression2016Ingår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 24, nr 8, s. 1311-1321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MexR is a repressor of the MexAB-OprM multidrug efflux pump operon of Pseudomonas aeruginosa, where DNA-binding impairing mutations lead to multidrug resistance (MDR). Surprisingly, the crystal structure of an MDR-conferring MexR mutant R21W (2.19 angstrom) presented here is closely similar to wildtype MexR. However, our extended analysis, by molecular dynamics and small-angle X-ray scattering, reveals that the mutation stabilizes a ground state that is deficient of DNA binding and is shared by both mutant and wild-type MexR, whereas the DNA-binding state is only transiently reached by the more flexible wild-type MexR. This population shift in the conformational ensemble is effected by mutation-induced allosteric coupling of contact networks that are independent in the wild-type protein. We propose that the MexR-R21W mutant mimics derepression by small-molecule binding to MarR proteins, and that the described allosteric model based on population shifts may also apply to other MarR family members.

  • 7.
    Andrésen, Cecilia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Helander, Sara
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Lemak, Alexander
    University of Toronto, Canada .
    Fares, Christophe
    University of Toronto, Canada .
    Csizmok, Veronika
    Hospital for Sick Children, Canada .
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Penn, Linda Z
    University of Toronto, Canada .
    Forman-Kay, Julie D
    Hospital Sick Children, Canada University of Toronto, Canada .
    Arrowsmith, Cheryl H
    University of Toronto, Canada.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding2012Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr 13, s. 6353-6366Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein. By nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements and NOE analysis, we show that although Myc occupies a very heterogeneous conformational space, we find transiently structured regions in residues 22-33 and in the Myc homology box I (MBI; residues 45-65); both these regions are conserved in other members of the Myc family. Binding of Bin1 to Myc-1-88 as assayed by NMR and surface plasmon resonance (SPR) revealed primary binding to the S62 region in a dynamically disordered and multivalent complex, accompanied by population shifts leading to altered intramolecular conformational dynamics. These findings expand the increasingly recognized concept of intrinsically disordered regions mediating transient interactions to Myc, a key transcriptional regulator of major medical importance, and have important implications for further understanding its multifaceted role in gene regulation.

  • 8.
    Andrésen, Cecilia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Niklasson, Markus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Cassman Eklöf, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Biophysical characterization of the calmodulin-like domain of Plasmodium falciparum calcium dependent protein kinase 32017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 7, artikel-id e0181721Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Calcium dependent protein kinases are unique to plants and certain parasites and comprise an N-terminal segment and a kinase domain that is regulated by a C-terminal calcium binding domain. Since the proteins are not found in man they are potential drug targets. We have characterized the calcium binding lobes of the regulatory domain of calcium dependent protein kinase 3 from the malaria parasite Plasmodium falciparum. Despite being structurally similar, the two lobes differ in several other regards. While the monomeric N-terminal lobe changes its structure in response to calcium binding and shows global dynamics on the sub-millisecond time-scale both in its apo and calcium bound states, the C-terminal lobe could not be prepared calcium-free and forms dimers in solution. If our results can be generalized to the full-length protein, they suggest that the C-terminal lobe is calcium bound even at basal levels and that activation is caused by the structural reorganization associated with binding of a single calcium ion to the N-terminal lobe.

  • 9.
    Augusto Berrocal, Jose
    et al.
    Eindhoven University of Technology, Netherlands.
    Di Meo, Florent
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk kemi. Linköpings universitet, Tekniska fakulteten. University of Limoges, France.
    Garcia-Iglesias, Miguel
    Eindhoven University of Technology, Netherlands.
    Gosens, Ronald P. J.
    Eindhoven University of Technology, Netherlands.
    Meijer, E. W.
    Eindhoven University of Technology, Netherlands.
    Linares, Mathieu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Palmans, Anja R. A.
    Eindhoven University of Technology, Netherlands.
    Consequences of conformational flexibility in hydrogen-bond-driven self-assembly processes2016Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, nr 72, s. 10870-10873Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the synthesis and self-assembly of chiral, conformationally flexible C-3-symmetrical trisamides. A strong Cotton effect is observed for the supramolecular polymers in linear alkanes but not in cyclic alkanes. MD simulations suggest 2:1 conformations of the amides within the aggregates in both types of solvents, but a chiral bias in only linear alkanes.

  • 10.
    Bano-Polo, Manuel
    et al.
    University of Valencia, Spain .
    Martinez-Gill, Luis
    University of Valencia, Spain .
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Nieva, Jose L.
    University of Pais Vasco UPV EHU, Spain .
    Elofsson, Arne
    Stockholm University, Sweden .
    Mingarro, Ismael
    University of Valencia, Spain .
    Charge Pair Interactions in Transmembrane Helices and Turn Propensity of the Connecting Sequence Promote Helical Hairpin Insertion2013Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 425, nr 4, s. 830-840Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    alpha-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.

  • 11.
    Barrientos-Somarribas, Mauricio
    et al.
    Karolinska Inst, Sweden.
    Messina, David N.
    Stockholm Univ, Sweden.
    Pou, Christian
    Karolinska Inst, Sweden.
    Lysholm, Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Bjerkner, Annelie
    Karolinska Univ Hosp, Sweden.
    Allander, Tobias
    Karolinska Univ Hosp, Sweden.
    Andersson, Björn
    Karolinska Inst, Sweden.
    Sonnhammer, Erik L. L.
    Stockholm Univ, Sweden.
    Discovering viral genomes in human metagenomic data by predicting unknown protein families2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Massive amounts of metagenomics data are currently being produced, and in all such projects a sizeable fraction of the resulting data shows no or little homology to known sequences. It is likely that this fraction contains novel viruses, but identification is challenging since they frequently lack homology to known viruses. To overcome this problem, we developed a strategy to detect ORFan protein families in shotgun metagenomics data, using similarity-based clustering and a set of filters to extract bona fide protein families. We applied this method to 17 virus-enriched libraries originating from human nasopharyngeal aspirates, serum, feces, and cerebrospinal fluid samples. This resulted in 32 predicted putative novel gene families. Some families showed detectable homology to sequences in metagenomics datasets and protein databases after reannotation. Notably, one predicted family matches an ORF from the highly variable Torque Teno virus (TTV). Furthermore, follow-up from a predicted ORFan resulted in the complete reconstruction of a novel circular genome. Its organisation suggests that it most likely corresponds to a novel bacteriophage in the microviridae family, hence it was named bacteriophage HFM.

  • 12.
    Basu, Sankar
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Bhattacharyya, Dhananjay
    Computational Science Division, Saha Insititute of Nuclear Physics, Kolkata 700064, India.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    SARAMAint: The Complementarity Plot for Protein–Protein Interface2014Ingår i: Journal of Bioinformatics and Intelligent Control, Vol. 3Artikel i tidskrift (Refereegranskat)
  • 13.
    Basu, Sankar Chandra
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten. University of Calcutta, India.
    Söderquist, Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Proteus: a random forest classifier to predict disorder-to-order transitioning binding regions in intrinsically disordered proteins2017Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 31, nr 5, s. 453-466Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The focus of the computational structural biology community has taken a dramatic shift over the past one-and-a-half decades from the classical protein structure prediction problem to the possible understanding of intrinsically disordered proteins (IDP) or proteins containing regions of disorder (IDPR). The current interest lies in the unraveling of a disorder-to-order transitioning code embedded in the amino acid sequences of IDPs/ IDPRs. Disordered proteins are characterized by an enormous amount of structural plasticity which makes them promiscuous in binding to different partners, multi-functional in cellular activity and atypical in folding energy landscapes resembling partially folded molten globules. Also, their involvement in several deadly human diseases (e.g. cancer, cardiovascular and neurodegenerative diseases) makes them attractive drug targets, and important for a biochemical understanding of the disease(s). The study of the structural ensemble of IDPs is rather difficult, in particular for transient interactions. When bound to a structured partner, an IDPR adapts an ordered conformation in the complex. The residues that undergo this disorder-to-order transition are called protean residues, generally found in short contiguous stretches and the first step in understanding the modus operandi of an IDP/IDPR would be to predict these residues. There are a few available methods which predict these protean segments from their amino acid sequences; however, their performance reported in the literature leaves clear room for improvement. With this background, the current study presents Proteus, a random forest classifier that predicts the likelihood of a residue undergoing a disorder-toorder transition upon binding to a potential partner protein. The prediction is based on features that can be calculated using the amino acid sequence alone. Proteus compares favorably with existing methods predicting twice as many true positives as the second best method (55 vs. 27%) with a much higher precision on an independent data set. The current study also sheds some light on a possible disorderto-order transitioning consensus, untangled, yet embedded in the amino acid sequence of IDPs. Some guidelines have also been suggested for proceeding with a real-life structural modeling involving an IDPR using Proteus.

  • 14.
    Basu, Sankar Chandra
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    DockQ: A Quality Measure for Protein-Protein Docking Models2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 8, s. e0161879-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: F-nat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (amp;gt; 10 angstrom) might still qualify as acceptable with a descent F-nat (amp;gt; 0.50) and iRMS (amp;lt; 3.0 angstrom). This is also the reason why the so called CAPRI criteria for assessing the quality of docking models is defined by applying various ad-hoc cutoffs on these measures to classify a docking model into the four classes: Incorrect, Acceptable, Medium, or High quality. This classification has been useful in CAPRI, but since models are grouped in only four bins it is also rather limiting, making it difficult to rank models, correlate with scoring functions or use it as target function in machine learning algorithms. Here, we present DockQ, a continuous protein-protein docking model quality measure derived by combining F-nat, LRMS, and iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for protein structure prediction, and DockQ should be useful in a similar development in the protein docking field.

  • 15.
    Basu, Sankar Chandra
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Finding correct protein-protein docking models using ProQDock2016Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 12, s. 262-270Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Protein-protein interactions are a key in virtually all biological processes. For a detailed understanding of the biological processes, the structure of the protein complex is essential. Given the current experimental techniques for structure determination, the vast majority of all protein complexes will never be solved by experimental techniques. In lack of experimental data, computational docking methods can be used to predict the structure of the protein complex. A common strategy is to generate many alternative docking solutions (atomic models) and then use a scoring function to select the best. The success of the computational docking technique is, to a large degree, dependent on the ability of the scoring function to accurately rank and score the many alternative docking models. Results: Here, we present ProQDock, a scoring function that predicts the absolute quality of docking model measured by a novel protein docking quality score (DockQ). ProQDock uses support vector machines trained to predict the quality of protein docking models using features that can be calculated from the docking model itself. By combining different types of features describing both the protein-protein interface and the overall physical chemistry, it was possible to improve the correlation with DockQ from 0.25 for the best individual feature (electrostatic complementarity) to 0.49 for the final version of ProQDock. ProQDock performed better than the state-of-the-art methods ZRANK and ZRANK2 in terms of correlations, ranking and finding correct models on an independent test set. Finally, we also demonstrate that it is possible to combine ProQDock with ZRANK and ZRANK2 to improve performance even further.

  • 16.
    Beecham, Ashley H.
    et al.
    University of Miami, FL USA .
    Patsopoulos, Nikolaos A.
    Brigham and Womens Hospital, MA USA .
    Xifara, Dionysia K.
    University of Oxford, England .
    Davis, Mary F.
    Vanderbilt University, TN USA .
    Kemppinen, Anu
    University of Cambridge, England .
    Cotsapas, Chris
    Broad Institute Harvard and MIT, MA USA .
    Shah, Tejas S.
    Wellcome Trust Sanger Institute, England .
    Spencer, Chris
    University of Oxford, England .
    Booth, David
    University of Sydney, Australia .
    Goris, An
    Katholieke University of Leuven, Belgium .
    Oturai, Annette
    Copenhagen University Hospital, Denmark .
    Saarela, Janna
    University of Helsinki, Finland .
    Fontaine, Bertrand
    University of Paris 06, France .
    Hemmer, Bernhard
    Technical University of Munich, Germany .
    Martin, Claes
    Danderyd Hospital, Sweden .
    Zipp, Frauke
    Johannes Gutenberg University of Mainz, Germany .
    DAlfonso, Sandra
    University of Piemonte Orientale, Italy .
    Martinelli-Boneschi, Filippo
    Ist Science San Raffaele, Italy .
    Taylor, Bruce
    University of Tasmania, Australia .
    Harbo, Hanne F.
    Oslo University Hospital, Norway .
    Kockum, Ingrid
    Karolinska Institute, Sweden .
    Hillert, Jan
    Karolinska Institute, Sweden .
    Olsson, Tomas
    Karolinska Institute, Sweden .
    Ban, Maria
    University of Cambridge, England .
    Oksenberg, Jorge R.
    University of Calif San Francisco, CA USA .
    Hintzen, Rogier
    Erasmus University, Netherlands .
    F Barcellos, Lisa
    University of Calif Berkeley, CA 94720 USA .
    Agliardi, Cristina
    IRCCS Santa Maria Nascente, Italy .
    Alfredsson, Lars
    Karolinska Institute, Sweden .
    Alizadeh, Mehdi
    University of Rennes 1, France .
    Anderson, Carl
    Wellcome Trust Sanger Institute, England .
    Andrews, Robert
    Wellcome Trust Sanger Institute, England .
    Bach Sondergaard, Helle
    Copenhagen University Hospital, Denmark .
    Baker, Amie
    University of Cambridge, England .
    Band, Gavin
    University of Oxford, England .
    Baranzini, Sergio E.
    University of Calif San Francisco, CA USA .
    Barizzone, Nadia
    University of Piemonte Orientale, Italy .
    Barrett, Jeffrey
    Wellcome Trust Sanger Institute, England .
    Bellenguez, Celine
    University of Oxford, England .
    Bergamaschi, Laura
    University of Piemonte Orientale, Italy .
    Bernardinelli, Luisa
    MRC, England .
    Berthele, Achim
    Technical University of Munich, Germany .
    Biberacher, Viola
    Technical University of Munich, Germany .
    Binder, Thomas M C.
    University of Medical Centre Hamburg Eppendorf, Germany .
    Blackburn, Hannah
    Wellcome Trust Sanger Institute, England .
    Bomfim, Izaura L.
    Karolinska Institute, Sweden .
    Brambilla, Paola
    Ist Science San Raffaele, Italy .
    Broadley, Simon
    Griffith University, Australia .
    Brochet, Bruno
    University of Bordeaux 2, France .
    Brundin, Lou
    Karolinska Institute, Sweden .
    Buck, Dorothea
    Technical University of Munich, Germany .
    Butzkueven, Helmut
    University of Melbourne, Australia .
    Caillier, Stacy J.
    University of Calif San Francisco, CA USA .
    Camu, William
    Centre Hospital University of Regional Montpellier, France .
    Carpentier, Wassila
    University of Paris 06, France .
    Cavalla, Paola
    Azienda Osped Citta Salute and Science Torino, Italy .
    Celius, Elisabeth G.
    Oslo University Hospital, Norway .
    Coman, Irene
    Hop Avicenne, France .
    Comi, Giancarlo
    Ist Science San Raffaele, Italy .
    Corrado, Lucia
    University of Piemonte Orientale, Italy .
    Cosemans, Leentje
    Katholieke University of Leuven, Belgium .
    Cournu-Rebeix, Isabelle
    University of Paris 06, France .
    Cree, Bruce A C.
    University of Calif San Francisco, CA USA .
    Cusi, Daniele
    University of Milan, Italy .
    Damotte, Vincent
    University of Paris 06, France .
    Defer, Gilles
    CHU Caen, France .
    Delgado, Silvia R.
    University of Miami, FL USA .
    Deloukas, Panos
    Wellcome Trust Sanger Institute, England .
    di Sapio, Alessia
    University of San Luigi, Italy .
    Dilthey, Alexander T.
    University of Oxford, England .
    Donnelly, Peter
    University of Oxford, England .
    Dubois, Benedicte
    Katholieke University of Leuven, Belgium .
    Duddy, Martin
    Royal Victoria Infirm, England .
    Edkins, Sarah
    Wellcome Trust Sanger Institute, England .
    Elovaara, Irina
    University of Tampere, Finland .
    Esposito, Federica
    Ist Science San Raffaele, Italy .
    Evangelou, Nikos
    University of Nottingham Hospital, England .
    Fiddes, Barnaby
    University of Cambridge, England .
    Field, Judith
    University of Melbourne, Australia .
    Franke, Andre
    University of Kiel, Germany .
    Freeman, Colin
    University of Oxford, England .
    Frohlich, Irene Y.
    Brigham and Womens Hospital, MA USA .
    Galimberti, Daniela
    University of Milan, Italy .
    Gieger, Christian
    German Research Centre Environm Heatlh, Germany .
    Gourraud, Pierre-Antoine
    University of Calif San Francisco, CA USA .
    Graetz, Christiane
    Johannes Gutenberg University of Mainz, Germany .
    Graham, Andrew
    Ipswich Hospital National Health Serv NHS Trust, England .
    Grummel, Verena
    Technical University of Munich, Germany .
    Guaschino, Clara
    Ist Science San Raffaele, Italy .
    Hadjixenofontos, Athena
    University of Miami, FL USA .
    Hakonarson, Hakon
    Childrens Hospital Philadelphia, PA USA .
    Halfpenny, Christopher
    Southampton Gen Hospital, England .
    Hall, Gillian
    Aberdeen Royal Infirm, Scotland .
    Hall, Per
    Karolinska Institute, Sweden .
    Hamsten, Anders
    Karolinska University Hospital Solna, Sweden .
    Harley, James
    Hull Royal Infirm, England .
    Harrower, Timothy
    Royal Devon and Exeter Fdn Trust Hospital, England .
    Hawkins, Clive
    Keele University, England .
    Hellenthal, Garrett
    UCL, England .
    Hillier, Charles
    Poole Gen Hospital, England .
    Hobart, Jeremy
    University of Plymouth, England .
    Hoshi, Muni
    Technical University of Munich, Germany .
    Hunt, Sarah E.
    Wellcome Trust Sanger Institute, England .
    Jagodic, Maja
    Karolinska Institute, Sweden .
    Jelcic, Ilijas
    University of Medical Centre Hamburg Eppendorf, Germany .
    Jochim, Angela
    Technical University of Munich, Germany .
    Kendall, Brian
    Leicester Royal Infirm, England .
    Kermode, Allan
    University of Western Australia, Australia .
    Kilpatrick, Trevor
    University of Melbourne, Australia .
    Koivisto, Keijo
    Seinajoki Central Hospital, Finland .
    Konidari, Ioanna
    University of Miami, FL USA .
    Korn, Thomas
    Technical University of Munich, Germany .
    Kronsbein, Helena
    Technical University of Munich, Germany .
    Langford, Cordelia
    Wellcome Trust Sanger Institute, England .
    Larsson, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Lathrop, Mark
    Centre Etud Polymorphisme Humain, France .
    Lebrun-Frenay, Christine
    CHRU Nice, France .
    Lechner-Scott, Jeannette
    University of Newcastle, Australia .
    Lee, Michelle H.
    Brigham and Womens Hospital, MA USA .
    Leone, Maurizio A.
    Osped Maggiore Novara, Italy .
    Leppa, Virpi
    University of Helsinki, Finland .
    Liberatore, Giuseppe
    Ist Science San Raffaele, Italy .
    Lie, Benedicte A.
    University of Oslo, Norway .
    Lill, Christina M.
    Johannes Gutenberg University of Mainz, Germany .
    Linden, Magdalena
    Karolinska Institute, Sweden .
    Link, Jenny
    Karolinska Institute, Sweden .
    Luessi, Felix
    Johannes Gutenberg University of Mainz, Germany .
    Lycke, Jan
    University of Gothenburg, Sweden .
    Macciardi, Fabio
    University of Calif Irvine, CA USA .
    Mannisto, Satu
    National Institute Health and Welf, Finland .
    Manrique, Clara P.
    University of Miami, FL USA .
    Martin, Roland
    University of Medical Centre Hamburg Eppendorf, Germany .
    Martinelli, Vittorio
    Ist Science San Raffaele, Italy .
    Mason, Deborah
    Canterbury Dist Health Board, New Zealand .
    Mazibrada, Gordon
    Queen Elizabeth Medical Centre, England .
    McCabe, Cristin
    Broad Institute Harvard and MIT, MA USA .
    Mero, Inger-Lise
    Oslo University Hospital, Norway .
    Mescheriakova, Julia
    Erasmus University, Netherlands .
    Moutsianas, Loukas
    University of Oxford, England .
    Myhr, Kjell-Morten
    Haukeland Hospital, Norway .
    Nagels, Guy
    National Multiple Sclerosis Centre Melsbroek, Belgium .
    Nicholas, Richard
    Charing Cross Hospital, England .
    Nilsson, Petra
    Lund University, Sweden .
    Piehl, Fredrik
    Karolinska Institute, Sweden .
    Pirinen, Matti
    University of Oxford, England .
    Price, Sian E.
    Royal Hallamshire Hospital, England .
    Quach, Hong
    University of Calif Berkeley, CA USA .
    Reunanen, Mauri
    University of Oulu, Finland .
    Robberecht, Wim
    Vesalius Research Centre, Belgium .
    Robertson, Neil P.
    Cardiff University, Wales .
    Rodegher, Mariaemma
    Ist Science San Raffaele, Italy .
    Rog, David
    Salford Royal NHS Fdn Trust, England .
    Salvetti, Marco
    University of Roma La Sapienza, Italy .
    Schnetz-Boutaud, Nathalie C.
    Vanderbilt University, TN USA .
    Sellebjerg, Finn
    Copenhagen University Hospital, Denmark .
    Selter, Rebecca C.
    Technical University of Munich, Germany .
    Schaefer, Catherine
    Kaiser Permanente Div Research, CA USA .
    Shaunak, Sandip
    Royal Preston Hospital, England .
    Shen, Ling
    Kaiser Permanente Div Research, CA USA .
    Shields, Simon
    Norfolk and Norwich Hospital, England .
    Siffrin, Volker
    Johannes Gutenberg University of Mainz, Germany .
    Slee, Mark
    Flinders University of S Australia, Australia .
    Soelberg Sorensen, Per
    Copenhagen University Hospital, Denmark .
    Sorosina, Melissa
    Ist Science San Raffaele, Italy .
    Sospedra, Mireia
    University of Medical Centre Hamburg Eppendorf, Germany .
    Spurkland, Anne
    University of Oslo, Norway .
    Strange, Amy
    University of Oxford, England .
    Sundqvist, Emilie
    Karolinska Institute, Sweden .
    Thijs, Vincent
    Vesalius Research Centre, Belgium .
    Thorpe, John
    Peterborough City Hospital, England .
    Ticca, Anna
    San Francesco Hospital, Italy .
    Tienari, Pentti
    University of Helsinki, Finland .
    van Duijn, Cornelia
    Erasmus MC, Netherlands .
    Visser, Elizabeth M.
    University of Aberdeen, Scotland .
    Vucic, Steve
    University of Sydney, Australia .
    Westerlind, Helga
    Karolinska Institute, Sweden .
    Wiley, James S.
    University of Melbourne, Australia .
    Wilkins, Alastair
    University of Bristol, England .
    Wilson, James F.
    University of Edinburgh, Scotland .
    Winkelmann, Juliane
    Technical University of Munich, Germany .
    Zajicek, John
    University of Plymouth, England .
    Zindler, Eva
    Johannes Gutenberg University of Mainz, Germany .
    Haines, Jonathan L.
    Vanderbilt University, TN USA .
    Pericak-Vance, Margaret A.
    University of Miami, FL USA .
    Ivinson, Adrian J.
    Harvard University, MA USA .
    Stewart, Graeme
    University of Sydney, Australia .
    Hafler, David
    Broad Institute Harvard and MIT, MA USA .
    Hauser, Stephen L.
    University of Calif San Francisco, CA USA .
    Compston, Alastair
    University of Cambridge, England .
    McVean, Gil
    University of Oxford, England .
    De Jager, Philip
    Brigham and Womens Hospital, MA USA .
    Sawcer, Stephen J.
    University of Cambridge, England .
    McCauley, Jacob L.
    University of Miami, FL USA .
    Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis2013Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 11, s. 1353-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P andlt; 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P andlt; 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

  • 17.
    Berggren, Karl-Fredrik
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Fysik. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    20 years in HPC 1989-20092009Övrigt (Övrig (populärvetenskap, debatt, mm))
  • 18.
    Bergqvist, Jonathan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Study of Protein Interfaces with Clustering2018Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Protein-protein interactions occur in nature and have different functions. The interacting surface between two interacting proteins contains the respective protein's interface residues.

    In this thesis, a series of Python scripts are presented which can perform interface-interface comparisons with the method InterComp, to obtain a distance matrix of different protein interfaces. The distance matrix can be studied with the use of clustering algorithms such as DBSCAN.

    The result from clustering using DBSCAN shows that for the 77,017 protein interfaces studied, a majority of the protein interfaces are part of a single cluster while most of the remaining interfaces are noise for the tested parameters Eps and MinPts.

    The conclusion of this thesis is the effect on the number of clusters for the tested parameters Eps and MinPts when performing DBSCAN.

  • 19.
    Bhattacharyya, Dhananjay
    et al.
    Saha Institute Nucl Phys, India.
    Halder, Sukanya
    Saha Institute Nucl Phys, India.
    Basu, Sankar Chandra
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten. University of Calcutta, India.
    Mukherjee, Debasish
    Saha Institute Nucl Phys, India.
    Kumar, Prasun
    Indian Institute Science, India.
    Bansal, Manju
    Indian Institute Science, India.
    RNAHelix: computational modeling of nucleic acid structures with Watson-Crick and non-canonical base pairs2017Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 31, nr 2, s. 219-235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Comprehensive analyses of structural features of non-canonical base pairs within a nucleic acid double helix are limited by the availability of a small number of three dimensional structures. Therefore, a procedure for model building of double helices containing any given nucleotide sequence and base pairing information, either canonical or non-canonical, is seriously needed. Here we describe a program RNAHelix, which is an updated version of our widely used software, NUCGEN. The program can regenerate duplexes using the dinucleotide step and base pair orientation parameters for a given double helical DNA or RNA sequence with defined Watson-Crick or non-Watson-Crick base pairs. The original structure and the corresponding regenerated structure of double helices were found to be very close, as indicated by the small RMSD values between positions of the corresponding atoms. Structures of several usual and unusual double helices have been regenerated and compared with their original structures in terms of base pair RMSD, torsion angles and electrostatic potentials and very high agreements have been noted. RNAHelix can also be used to generate a structure with a sequence completely different from an experimentally determined one or to introduce single to multiple mutation, but with the same set of parameters and hence can also be an important tool in homology modeling and study of mutation induced structural changes.

  • 20.
    Bittmann, Simon F.
    et al.
    Max Planck Inst Struct and Dynam Matter, Germany.
    Dsouza, Raison
    Max Planck Inst Struct and Dynam Matter, Germany; Univ Hamburg, Germany.
    Siddiqui, Khalid M.
    Max Planck Inst Struct and Dynam Matter, Germany.
    Hayes, Stuart A.
    Max Planck Inst Struct and Dynam Matter, Germany.
    Rossos, Andreas
    Max Planck Inst Struct and Dynam Matter, Germany.
    Corthey, Gaston
    Max Planck Inst Struct and Dynam Matter, Germany; Univ Nacl San Martin, Argentina.
    Kochman, Michal
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten. Max Planck Inst Struct and Dynam Matter, Germany.
    Prokhorenko, Valentyn I.
    Max Planck Inst Struct and Dynam Matter, Germany.
    Murphy, R. Scott
    Univ Regina, Canada.
    Schwoerer, Heinrich
    Max Planck Inst Struct and Dynam Matter, Germany.
    Miller, R. J. Dwayne
    Max Planck Inst Struct and Dynam Matter, Germany; Univ Toronto, Canada; Univ Toronto, Canada.
    Ultrafast ring-opening and solvent-dependent product relaxation of photochromic spironaphthopyran2019Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 21, nr 33, s. 18119-18127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ultrafast dynamics of unsubstituted spironaphthopyran (SNP) were investigated using femtosecond transient UV and visible absorption spectroscopy in three different solvents and by semi-classical nuclear dynamics simulations. The primary ring-opening of the pyran unit was found to occur in 300 fs yielding a non-planar intermediate in the first singlet excited state (S-1). Subsequent planarisation and relaxation to the product ground state proceed through barrier crossing on the S-1 potential energy surface (PES) and take place within 1.1 ps after excitation. Simulations show that more than 90% of the trajectories involving C-O bond elongation lead to the planar, open-ring product, while relaxation back to the S-0 of the closed-ring form is accompanied by C-N elongation. All ensuing spectral dynamics are ascribed to vibrational relaxation and thermalisation of the product with a time constant of 13 ps. The latter shows dependency on characteristics of the solvent with solvent relaxation kinetics playing a role.

  • 21.
    Borgmastars, Emmy
    et al.
    Umea Univ, Sweden.
    de Weerd, Hendrik Arnold
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten. Univ Skovde, Sweden.
    Lubovac-Pilav, Zelmina
    Univ Skovde, Sweden.
    Sund, Malin
    Umea Univ, Sweden.
    miRFA: an automated pipeline for microRNA functional analysis with correlation support from TCGA and TCPA expression data in pancreatic cancer2019Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, artikel-id 393Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundMicroRNAs (miRNAs) are small RNAs that regulate gene expression at a post-transcriptional level and are emerging as potentially important biomarkers for various disease states, including pancreatic cancer. In silico-based functional analysis of miRNAs usually consists of miRNA target prediction and functional enrichment analysis of miRNA targets. Since miRNA target prediction methods generate a large number of false positive target genes, further validation to narrow down interesting candidate miRNA targets is needed. One commonly used method correlates miRNA and mRNA expression to assess the regulatory effect of a particular miRNA.The aim of this study was to build a bioinformatics pipeline in R for miRNA functional analysis including correlation analyses between miRNA expression levels and its targets on mRNA and protein expression levels available from the cancer genome atlas (TCGA) and the cancer proteome atlas (TCPA). TCGA-derived expression data of specific mature miRNA isoforms from pancreatic cancer tissue was used.ResultsFifteen circulating miRNAs with significantly altered expression levels detected in pancreatic cancer patients were queried separately in the pipeline. The pipeline generated predicted miRNA target genes, enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Predicted miRNA targets were evaluated by correlation analyses between each miRNA and its predicted targets. MiRNA functional analysis in combination with Kaplan-Meier survival analysis suggest that hsa-miR-885-5p could act as a tumor suppressor and should be validated as a potential prognostic biomarker in pancreatic cancer.ConclusionsOur miRNA functional analysis (miRFA) pipeline can serve as a valuable tool in biomarker discovery involving mature miRNAs associated with pancreatic cancer and could be developed to cover additional cancer types. Results for all mature miRNAs in TCGA pancreatic adenocarcinoma dataset can be studied and downloaded through a shiny web application at https://emmbor.shinyapps.io/mirfa/.

  • 22.
    Bresel, Anders
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    GenomeLKPG: A comprehensive proteome sequencedatabase for taxonomy studies2008Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In order to perform taxonomically unbiased analyses of protein relationships, there is a need ofcomplete proteomes rather than databases with bias towards well characterized protein families. However, nocomprehensive resource of completed proteomes is currently available. Instead, the proteomes need to be down-loaded manually from di®erent servers, all using different filename conventions and fasta header formats.

    Results: We have developed a semi-automatic algorithm that retrieves complete proteomes from multiple FTP-servers and maps the species-speci¯c sequence entries to the NCBI taxonomy. The compiled data is provided ina sequence database named genomeLKPG.

    Conclusions: The usefulness of genomeLKPG is proven in several published taxonomical studies.

  • 23.
    Bresell, Anders
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Characterization of protein families, sequence patterns, and functional annotations in large data sets2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Bioinformatics involves storing, analyzing and making predictions on massive amounts of protein and nucleotide sequence data. The thesis consists of six papers and is focused on proteins. It describes the utilization of bioinformatics techniques to characterize protein families and to detect patterns in gene expression and in polypeptide occurrences. Two protein families were bioinformatically characterized - the membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) and the Tripartite motif (TRIM) protein families.

    In the study of the MAPEG super-family, application of different bioinformatic methods made it possible to characterize many new members leading to a doubling of the family size. Furthermore, the MAPEG members were subdivided into families. Remarkably, in six families with previously predominantly mammalian members, fish representatives were also now detected, which dated the origin of these families back to the Cambrium ”species explosion”, thus earlier than previously anticipated. Sequence comparisons made it possible to define diagnostic sequence patterns that can be used in genome annotations. Upon publication of several MAPEG structures, these patterns were confirmed to be part of the active sites.

    In the TRIM study, the bioinformatic analyses made it possible to subdivide the proteins into three subtypes and to characterize a large number of members. In addition, the analyses showed crucial structural dependencies between the RING and the B-box domains of the TRIM member

    Ro52. The linker region between the two domains, denoted RBL, is known

    to be disease associated. Now, an amphipathic helix was found to be a

    characteristic feature of the RBL region, which also was used to divide the family into three subtypes.

    The ontology annotation treebrowser (OAT) tool was developed to detect functional similarities or common concepts in long lists of proteins or genes, typically generated from proteomics or microarray experiments. OAT was the first annotation browser to include both Gene Ontology (GO) and Medical Subject Headings (MeSH) into the same framework. The complementarity of these two ontologies was demonstrated. OAT was used in the TRIM study to detect differences in functional annotations between the subtypes.

    In the oligopeptide study, we investigated pentapeptide patterns that were over- or under-represented in the current de facto standard database of protein knowledge and a set of completed genomes, compared to what could be expected from amino acid compositions. We found three predominant categories of patterns: (i) patterns originating from frequently occurring families, e.g. respiratory chain-associated proteins and translation machinery proteins; (ii) proteins with structurally and/or functionally favored patterns; (iii) multicopy species-specific retrotransposons, only found in the genome set. Such patterns may influence amino acid residue based prediction algorithms. These findings in the oligopeptide study were utilized for development of a new method that detects translated introns in unverified protein predictions, which are available in great numbers due to the many completed and ongoing genome projects.

    A new comprehensive database of protein sequences from completed genomes was developed, denoted genomeLKPG. This database was of central importance in the MAPEG, TRIM and oligopeptide studies. The new sequence database has also been proven useful in several other studies.

    Delarbeten
    1. Bioinformatic and enzymatic characterization of the MAPEG superfamily
    Öppna denna publikation i ny flik eller fönster >>Bioinformatic and enzymatic characterization of the MAPEG superfamily
    Visa övriga...
    2005 (Engelska)Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 272, nr 7, s. 1688-1703Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily includes structurally related membrane proteins with diverse functions of widespread origin. A total of 136 proteins belonging to the MAPEG superfamily were found in database and genome screenings. The members were found in prokaryotes and eukaryotes, but not in any archaeal organism. Multiple sequence alignments and calculations of evolutionary trees revealed a clear subdivision of the eukaryotic MAPEG members, corresponding to the six families of microsomal glutathione transferases (MGST) 1, 2 and 3, leukotriene C4 synthase (LTC4), 5-lipoxygenase activating protein (FLAP), and prostaglandin E synthase. Prokaryotes contain at least two distinct potential ancestral subfamilies, of which one is unique, whereas the other most closely resembles enzymes that belong to the MGST2/FLAP/LTC4 synthase families. The insect members are most similar to MGST1/prostaglandin E synthase. With the new data available, we observe that fish enzymes are present in all six families, showing an early origin for MAPEG family differentiation. Thus, the evolutionary origins and relationships of the MAPEG superfamily can be defined, including distinct sequence patterns characteristic for each of the subfamilies. We have further investigated and functionally characterized representative gene products from Escherichia coli, Synechocystis sp., Arabidopsis thaliana and Drosophila melanogaster, and the fish liver enzyme, purified from pike (Esox lucius). Protein overexpression and enzyme activity analysis demonstrated that all proteins catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione. The E. coli protein displayed glutathione transferase activity of 0.11 µmol·min−1·mg−1 in the membrane fraction from bacteria overexpressing the protein. Partial purification of the Synechocystis sp. protein yielded an enzyme of the expected molecular mass and an N-terminal amino acid sequence that was at least 50% pure, with a specific activity towards 1-chloro-2,4-dinitrobenzene of 11 µmol·min−1·mg−1. Yeast microsomes expressing the Arabidopsis enzyme showed an activity of 0.02 µmol·min−1·mg−1, whereas the Drosophila enzyme expressed in E. coli was highly active at 3.6 µmol·min−1·mg−1. The purified pike enzyme is the most active MGST described so far with a specific activity of 285 µmol·min−1·mg−1. Drosophila and pike enzymes also displayed glutathione peroxidase activity towards cumene hydroperoxide (0.4 and 2.2 µmol·min−1·mg−1, respectively). Glutathione transferase activity can thus be regarded as a common denominator for a majority of MAPEG members throughout the kingdoms of life whereas glutathione peroxidase activity occurs in representatives from the MGST1, 2 and 3 and PGES subfamilies.

    Nyckelord
    MAPEG, microsomal glutathione transferase, prostaglandin, leukotriene
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12886 (URN)10.1111/j.1742-4658.2005.04596.x (DOI)
    Tillgänglig från: 2008-01-28 Skapad: 2008-01-28 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. The fellowship of the RING: The RING-B-box linker region (RBL) interacts with the RING in TRIM21/Ro52, contributes to an autoantigenic epitope in Sjögren's syndrome, and is an integral and conserved region in TRIM proteins
    Öppna denna publikation i ny flik eller fönster >>The fellowship of the RING: The RING-B-box linker region (RBL) interacts with the RING in TRIM21/Ro52, contributes to an autoantigenic epitope in Sjögren's syndrome, and is an integral and conserved region in TRIM proteins
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 377, nr 2, s. 431-449Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ro52 is a major autoantigen that is targeted in the autoimmune disease Sjögren syndrome and belongs to the tripartite motif (TRIM) protein family. Disease-related antigenic epitopes are mainly found in the coiled-coil domain of Ro52, but one such epitope is located in the Zn2+-binding region, which comprises an N-terminal RING followed by a B-box, separated by a ∼40-residue linker peptide. In the present study, we extend the structural, biophysical, and immunological knowledge of this RING-B-box linker (RBL) by employing an array of methods. Our bioinformatic investigations show that the RBL sequence motif is unique to TRIM proteins and can be classified into three distinct subtypes. The RBL regions of all three subtypes are as conserved as their known flanking domains, and all are predicted to comprise an amphipathic helix. This helix formation is confirmed by circular dichroism spectroscopy and is dependent on the presence of the RING. Immunological studies show that the RBL is part of a conformation-dependent epitope, and its antigenicity is likewise dependent on a structured RING domain. Recombinant Ro52 RING-RBL exists as a monomer in vitro, and binding of two Zn2+ increases its stability. Regions stabilized by Zn2+ binding are identified by limited proteolysis and matrix-assisted laser desorption/ionization mass spectrometry. Furthermore, the residues of the RING and linker that interact with each other are identified by analysis of protection patterns, which, together with bioinformatic and biophysical data, enabled us to propose a structural model of the RING-RBL based on modeling and docking experiments. Sequence similarities and evolutionary sequence patterns suggest that the results obtained from Ro52 are extendable to the entire TRIM protein family.

    Nyckelord
    Ro52; TRIM21; RING; linker; zinc binding
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12887 (URN)10.1016/j.jmb.2008.01.005 (DOI)
    Tillgänglig från: 2008-01-28 Skapad: 2008-01-28 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Ontology annotation treebrowser: an interactive tool where the complementarity of medical subject headings and gene ontology improves the interpretation of gene lists
    Öppna denna publikation i ny flik eller fönster >>Ontology annotation treebrowser: an interactive tool where the complementarity of medical subject headings and gene ontology improves the interpretation of gene lists
    2006 (Engelska)Ingår i: Applied Bioinformatics, ISSN 1175-5636, Vol. 5, nr 4, s. 225-236Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Gene expression and proteomics analysis allow the investigation of thousands of biomolecules in parallel. This results in a long list of interesting genes or proteins and a list of annotation terms in the order of thousands. It is not a trivial task to understand such a gene list and it would require extensive efforts to bring together the overwhelming amounts of associated information from the literature and databases. Thus, it is evident that we need ways of condensing and filtering this information. An excellent way to represent knowledge is to use ontologies, where it is possible to group genes or terms with overlapping context, rather than studying one-dimensional lists of keywords. Therefore, we have built the ontology annotation treebrowser (OAT) to represent, condense, filter and summarise the knowledge associated with a list of genes or proteins.

    The OAT system consists of two disjointed parts; a MySQL® database named OATdb, and a treebrowser engine that is implemented as a web interface. The OAT system is implemented using Perl scripts on an Apache web server and the gene, ontology and annotation data is stored in a relational MySQL® database. In OAT, we have harmonized the two ontologies of medical subject headings (MeSH) and gene ontology (GO), to enable us to use knowledge both from the literature and the annotation projects in the same tool. OAT includes multiple gene identifier sets, which are merged internally in the OAT database. We have also generated novel MeSH annotations by mapping accession numbers to MEDLINE entries.

    The ontology browser OAT was created to facilitate the analysis of gene lists. It can be browsed dynamically, so that a scientist can interact with the data and govern the outcome. Test statistics show which branches are enriched. We also show that the two ontologies complement each other, with surprisingly low overlap, by mapping annotations to the Unified Medical Language System®.

    We have developed a novel interactive annotation browser that is the first to incorporate both MeSH and GO for improved interpretation of gene lists. With OAT, we illustrate the benefits of combining MeSH and GO for understanding gene lists. OAT is available as a public web service at: http://www.ifm.liu.se/bioinfo/oat

    Nationell ämneskategori
    Teknik och teknologier
    Identifikatorer
    urn:nbn:se:liu:diva-12888 (URN)
    Tillgänglig från: 2008-01-28 Skapad: 2008-01-28 Senast uppdaterad: 2009-11-07Bibliografiskt granskad
    4. Characterization of oligopeptide patterns in large protein sets
    Öppna denna publikation i ny flik eller fönster >>Characterization of oligopeptide patterns in large protein sets
    2007 (Engelska)Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, nr 346, s. 1-15Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Recent sequencing projects and the growth of sequence data banks enable oligopeptide patterns to be characterized on a genome or kingdom level. Several studies have focused on kingdom or habitat classifications based on the abundance of short peptide patterns. There have also been efforts at local structural prediction based on short sequence motifs. Oligopeptide patterns undoubtedly carry valuable information content. Therefore, it is important to characterize these informational peptide patterns to shed light on possible new applications and the pitfalls implicit in neglecting bias in peptide patterns.

    Results: We have studied four classes of pentapeptide patterns (designated POP, NEP, ORP and URP) in the kingdoms archaea, bacteria and eukaryotes. POP are highly abundant patterns statistically not expected to exist; NEP are patterns that do not exist but are statistically expected to; ORP are patterns unique to a kingdom; and URP are patterns excluded from a kingdom. We used two data sources: the de facto standard of protein knowledge Swiss-Prot, and a set of 386 completely sequenced genomes. For each class of peptides we looked at the 100 most extreme and found both known and unknown sequence features. Most of the known sequence motifs can be explained on the basis of the protein families from which they originate.

    Conclusion: We find an inherent bias of certain oligopeptide patterns in naturally occurring proteins that cannot be explained solely on the basis of residue distribution in single proteins, kingdoms or databases. We see three predominant categories of patterns: (i) patterns widespread in a kingdom such as those originating from respiratory chain-associated proteins and translation machinery; (ii) proteins with structurally and/or functionally favored patterns, which have not yet been ascribed this role; (iii) multicopy species-specific retrotransposons, only found in the genome set. These categories will affect the accuracy of sequence pattern algorithms that rely mainly on amino acid residue usage. Methods presented in this paper may be used to discover targets for antibiotics, as we identify numerous examples of kingdom-specific antigens among our peptide classes. The methods may also be useful for detecting coding regions of genes.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12889 (URN)10.1186/1471-2164-8-346 (DOI)
    Tillgänglig från: 2008-01-28 Skapad: 2008-01-28 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Using SVM and tripeptide patterns to detect translated introns
    Öppna denna publikation i ny flik eller fönster >>Using SVM and tripeptide patterns to detect translated introns
    2007 (Engelska)Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12890 (URN)
    Tillgänglig från: 2008-01-28 Skapad: 2008-01-28 Senast uppdaterad: 2017-12-14
    6. GenomeLKPG: A comprehensive proteome sequencedatabase for taxonomy studies
    Öppna denna publikation i ny flik eller fönster >>GenomeLKPG: A comprehensive proteome sequencedatabase for taxonomy studies
    2008 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Abstract [en]

    Background: In order to perform taxonomically unbiased analyses of protein relationships, there is a need ofcomplete proteomes rather than databases with bias towards well characterized protein families. However, nocomprehensive resource of completed proteomes is currently available. Instead, the proteomes need to be down-loaded manually from di®erent servers, all using different filename conventions and fasta header formats.

    Results: We have developed a semi-automatic algorithm that retrieves complete proteomes from multiple FTP-servers and maps the species-speci¯c sequence entries to the NCBI taxonomy. The compiled data is provided ina sequence database named genomeLKPG.

    Conclusions: The usefulness of genomeLKPG is proven in several published taxonomical studies.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-52933 (URN)
    Tillgänglig från: 2010-01-13 Skapad: 2010-01-13 Senast uppdaterad: 2010-01-13
  • 24.
    Bresell, Anders
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Characterization of oligopeptide patterns in large protein sets2007Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, nr 346, s. 1-15Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Recent sequencing projects and the growth of sequence data banks enable oligopeptide patterns to be characterized on a genome or kingdom level. Several studies have focused on kingdom or habitat classifications based on the abundance of short peptide patterns. There have also been efforts at local structural prediction based on short sequence motifs. Oligopeptide patterns undoubtedly carry valuable information content. Therefore, it is important to characterize these informational peptide patterns to shed light on possible new applications and the pitfalls implicit in neglecting bias in peptide patterns.

    Results: We have studied four classes of pentapeptide patterns (designated POP, NEP, ORP and URP) in the kingdoms archaea, bacteria and eukaryotes. POP are highly abundant patterns statistically not expected to exist; NEP are patterns that do not exist but are statistically expected to; ORP are patterns unique to a kingdom; and URP are patterns excluded from a kingdom. We used two data sources: the de facto standard of protein knowledge Swiss-Prot, and a set of 386 completely sequenced genomes. For each class of peptides we looked at the 100 most extreme and found both known and unknown sequence features. Most of the known sequence motifs can be explained on the basis of the protein families from which they originate.

    Conclusion: We find an inherent bias of certain oligopeptide patterns in naturally occurring proteins that cannot be explained solely on the basis of residue distribution in single proteins, kingdoms or databases. We see three predominant categories of patterns: (i) patterns widespread in a kingdom such as those originating from respiratory chain-associated proteins and translation machinery; (ii) proteins with structurally and/or functionally favored patterns, which have not yet been ascribed this role; (iii) multicopy species-specific retrotransposons, only found in the genome set. These categories will affect the accuracy of sequence pattern algorithms that rely mainly on amino acid residue usage. Methods presented in this paper may be used to discover targets for antibiotics, as we identify numerous examples of kingdom-specific antigens among our peptide classes. The methods may also be useful for detecting coding regions of genes.

  • 25.
    Bresell, Anders
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Using SVM and tripeptide patterns to detect translated introns2007Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105Artikel i tidskrift (Refereegranskat)
  • 26.
    Bresell, Anders
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Servenius, Bo
    Biological Sciences, AstraZeneca R&D Lund, Sweden.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Ontology annotation treebrowser: an interactive tool where the complementarity of medical subject headings and gene ontology improves the interpretation of gene lists2006Ingår i: Applied Bioinformatics, ISSN 1175-5636, Vol. 5, nr 4, s. 225-236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene expression and proteomics analysis allow the investigation of thousands of biomolecules in parallel. This results in a long list of interesting genes or proteins and a list of annotation terms in the order of thousands. It is not a trivial task to understand such a gene list and it would require extensive efforts to bring together the overwhelming amounts of associated information from the literature and databases. Thus, it is evident that we need ways of condensing and filtering this information. An excellent way to represent knowledge is to use ontologies, where it is possible to group genes or terms with overlapping context, rather than studying one-dimensional lists of keywords. Therefore, we have built the ontology annotation treebrowser (OAT) to represent, condense, filter and summarise the knowledge associated with a list of genes or proteins.

    The OAT system consists of two disjointed parts; a MySQL® database named OATdb, and a treebrowser engine that is implemented as a web interface. The OAT system is implemented using Perl scripts on an Apache web server and the gene, ontology and annotation data is stored in a relational MySQL® database. In OAT, we have harmonized the two ontologies of medical subject headings (MeSH) and gene ontology (GO), to enable us to use knowledge both from the literature and the annotation projects in the same tool. OAT includes multiple gene identifier sets, which are merged internally in the OAT database. We have also generated novel MeSH annotations by mapping accession numbers to MEDLINE entries.

    The ontology browser OAT was created to facilitate the analysis of gene lists. It can be browsed dynamically, so that a scientist can interact with the data and govern the outcome. Test statistics show which branches are enriched. We also show that the two ontologies complement each other, with surprisingly low overlap, by mapping annotations to the Unified Medical Language System®.

    We have developed a novel interactive annotation browser that is the first to incorporate both MeSH and GO for improved interpretation of gene lists. With OAT, we illustrate the benefits of combining MeSH and GO for understanding gene lists. OAT is available as a public web service at: http://www.ifm.liu.se/bioinfo/oat

  • 27.
    Bresell, Anders
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Weinander, Rolf
    Department of Medicine, Division of Rheumatology Unit, Karolinska Institutet, Stockholm.
    Wiklund, Ronney
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Eriksson, Jan
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Jansson, Christer
    Department of Plant Biology & Forestry Genetics, Swedish Agricultural University, Uppsala.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Jakobsson, Per-Johan
    Department of Medicine, Division of Rheumatology Unit, Karolinska Institutet, Stockholm.
    Morgenstern, Ralf
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Lundqvist, Gerd
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Raza, Haider
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Shimoji, Miyuki
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Sun, Tie-Hua
    Institute of Environmental Medicine Karolinska Institutet, Stockholm.
    Balk, Lennart
    Stockholm Marine Research Centre, University of Stockholm.
    Bioinformatic and enzymatic characterization of the MAPEG superfamily2005Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 272, nr 7, s. 1688-1703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily includes structurally related membrane proteins with diverse functions of widespread origin. A total of 136 proteins belonging to the MAPEG superfamily were found in database and genome screenings. The members were found in prokaryotes and eukaryotes, but not in any archaeal organism. Multiple sequence alignments and calculations of evolutionary trees revealed a clear subdivision of the eukaryotic MAPEG members, corresponding to the six families of microsomal glutathione transferases (MGST) 1, 2 and 3, leukotriene C4 synthase (LTC4), 5-lipoxygenase activating protein (FLAP), and prostaglandin E synthase. Prokaryotes contain at least two distinct potential ancestral subfamilies, of which one is unique, whereas the other most closely resembles enzymes that belong to the MGST2/FLAP/LTC4 synthase families. The insect members are most similar to MGST1/prostaglandin E synthase. With the new data available, we observe that fish enzymes are present in all six families, showing an early origin for MAPEG family differentiation. Thus, the evolutionary origins and relationships of the MAPEG superfamily can be defined, including distinct sequence patterns characteristic for each of the subfamilies. We have further investigated and functionally characterized representative gene products from Escherichia coli, Synechocystis sp., Arabidopsis thaliana and Drosophila melanogaster, and the fish liver enzyme, purified from pike (Esox lucius). Protein overexpression and enzyme activity analysis demonstrated that all proteins catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione. The E. coli protein displayed glutathione transferase activity of 0.11 µmol·min−1·mg−1 in the membrane fraction from bacteria overexpressing the protein. Partial purification of the Synechocystis sp. protein yielded an enzyme of the expected molecular mass and an N-terminal amino acid sequence that was at least 50% pure, with a specific activity towards 1-chloro-2,4-dinitrobenzene of 11 µmol·min−1·mg−1. Yeast microsomes expressing the Arabidopsis enzyme showed an activity of 0.02 µmol·min−1·mg−1, whereas the Drosophila enzyme expressed in E. coli was highly active at 3.6 µmol·min−1·mg−1. The purified pike enzyme is the most active MGST described so far with a specific activity of 285 µmol·min−1·mg−1. Drosophila and pike enzymes also displayed glutathione peroxidase activity towards cumene hydroperoxide (0.4 and 2.2 µmol·min−1·mg−1, respectively). Glutathione transferase activity can thus be regarded as a common denominator for a majority of MAPEG members throughout the kingdoms of life whereas glutathione peroxidase activity occurs in representatives from the MGST1, 2 and 3 and PGES subfamilies.

  • 28.
    Bunkoczi, Gabor
    et al.
    University of Cambridge, England.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Read, Randy J.
    University of Cambridge, England.
    Local Error Estimates Dramatically Improve the Utility of Homology Models for Solving Crystal Structures by Molecular Replacement2015Ingår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, nr 2, s. 397-406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Predicted structures submitted for CASP10 have been evaluated as molecular replacement models against the corresponding sets of structure factor amplitudes. It has been found that the log- likelihood gain score computed for each prediction correlates well with common structure quality indicators but is more sensitive when the accuracy of the models is high. In addition, it was observed that using coordinate error estimates submitted by predictors to weight the model can improve its utility in molecular replacement dramatically, and several groups have been identified who reliably provide accurate error estimates that could be used to extend the application of molecular replacement for low-homology cases.

  • 29.
    Bzhalava, David
    et al.
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Ekström, Johanna
    Lund University, Malmö.
    Lysholm, Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Hultin, Emilie
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Faust, Helena
    Lund University, Malmö.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Lehtinen, Matti
    National Institute for Health and Welfare, Oulu, Finland.
    de Villiers, Ethel-Michele
    Deutsches Krebsforschungszentrum, Heidelberg, Germany.
    Dillner, Joakim
    Karolinska Institutet and Karolinska University Hospital, Stockholm.
    Phylogenetically diverse TT virus viremia among pregnant women2012Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 432, nr 2, s. 427-434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Infections during pregnancy have been suggested to be involved in childhood leukemias. We used high-throughput sequencing to describe the viruses most readily detectable in serum samples of pregnantwomen. Serum DNA of 112 mothers to leukemic children was amplified using whole genome amplification. Sequencing identified one TTvirus (TTV) isolate belonging to a known type and two putatively new TTVs. For 22 mothers, we also performed TTV amplification by general primer PCR before sequencing. This detected 39 TTVs, two of which were identical to the TTVs found after whole genome amplification.

    Altogether, we found 40 TTV isolates, 29 of which were putatively new types (similarities ranging from 89% to 69%). In conclusion, high throughput sequencing is useful to describe the known or unknown viruses that are present in serum samples of pregnantwomen.

  • 30.
    Bzhalava, Davit
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Johansson, Hanna
    Lund University, Malmö, Sweden.
    Ekstrom, Johanna
    Karolinska Institutet, Stockholm, Sweden.
    Faust, Helena
    Lund University, Malmö, Sweden.
    Moller, Birgitta
    Karolinska Institutet, Stockholm, Sweden.
    Eklund, Carina
    Karolinska Institutet, Stockholm, Sweden.
    Nordin, Peter
    Läkarhuset, Gothenburg, Sweden.
    Stenquist, Bo
    University of Gothenburg, Sweden.
    Paoli, John
    University of Gothenburg, Sweden.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Forslund, Ola
    Lund University, Malmö, Sweden.
    Dillner, Joakim
    Karolinska Institutet, Stockholm, Sweden.
    Unbiased Approach for Virus Detection in Skin Lesions2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To assess presence of virus DNA in skin lesions, swab samples from 82 squamous cell carcinomas of the skin (SCCs), 60 actinic keratoses (AKs), paraffin-embedded biopsies from 28 SCCs and 72 kerathoacanthomas (KAs) and fresh-frozen biopsies from 92 KAs, 85 SCCs and 92 AKs were analyzed by high throughput sequencing (HTS) using 454 or Ion Torrent technology. We found total of 4,284 viral reads, out of which 4,168 were Human Papillomavirus (HPV)-related, belonging to 15 known (HPV8, HPV12, HPV20, HPV36, HPV38, HPV45, HPV57, HPV59, HPV104, HPV105, HPV107, HPV109, HPV124, HPV138, HPV147), four previously described putative (HPV 915 F 06 007 FD1, FA73, FA101, SE42) and two putatively new HPV types (SE46, SE47). SE42 was cloned, sequenced, designated as HPV155 and found to have 76% similarity to the most closely related known HPV type. In conclusion, an unbiased approach for viral DNA detection in skin tumors has found that, although some new putative HPVs were found, known HPV types constituted most of the viral DNA.

  • 31.
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Mutational effects on protein structure and function2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In this thesis several important proteins are investigated from a structural perspective. Some of the proteins are disease related while other have important but not completely characterised functions. The techniques used are general as demonstrated by applications on metabolic proteins (CYP21, CYP11B1, IAPP, ADH3), regulatory proteins (p53, GDNF) and a transporter protein (ANTR1).

    When the protein CYP21 (steroid 21-hydroxylase) is deficient it causes CAH (congenital adrenal hyperplasia). For this protein, there are about 60 known mutations with characterised clinical phenotypes. Using manual structural analysis we managed to explain the severity of all but one of the mutations. By observing the properties of these mutations we could perform good predictions on, at the time, not classified mutations.

    For the cancer suppressor protein p53, there are over thousand mutations with known activity. To be able to analyse such a large number of mutations we developed an automated method for evaluation of the mutation effect called PREDMUT. In this method we include twelve different prediction parameters including two energy parameters calculated using an energy minimization procedure. The method manages to differentiate severe mutations from non-severe mutations with 77% accuracy on all possible single base substitutions and with 88% on mutations found in breast cancer patients.

    The automated prediction was further applied to CYP11B1 (steroid 11-beta-hydroxylase), which in a similar way as CYP21 causes CAH when deficient. A generalized method applicable to any kind of globular protein was developed. The method was subsequently evaluated on nine additional proteins for which mutants were known with annotated disease phenotypes. This prediction achieved 84% accuracy on CYP11B1 and 81% accuracy in total on the evaluation proteins while leaving 8% as unclassified. By increasing the number of unclassified mutations the accuracy of the remaining mutations could be increased on the evaluation proteins and substantially increase the classification quality as measured by the Matthews correlation coefficient. Servers with predictions for all possible single based substitutions are provided for p53, CYP21 and CYP11B1.

    The amyloid formation of IAPP (islet amyloid polypeptide) is strongly connected to diabetes and has been studied using both molecular dynamics and Monte Carlo energy minimization. The effects of mutations on the amount and speed of amyloid formation were investigated using three approaches. Applying a consensus of the three methods on a number of interesting mutations, 94% of the mutations could be correctly classified as amyloid forming or not, evaluated with in vitro measurements.

    In the brain there are many proteins whose functions and interactions are largely unknown. GDNF (glial cell line-derived neurotrophic factor) and NCAM (neural cell adhesion molecule) are two such neuron connected proteins that are known to interact. The form of interaction was studied using protein--protein docking where a docking interface was found mediated by four oppositely charged residues in respective protein. This interface was subsequently confirmed by mutagenesis experiments. The NCAM dimer interface upon binding to the GDNF dimer was also mapped as well as an additional interacting protein, GFRα1, which was successfully added to the protein complex without any clashes.

    A large and well studied protein family is the alcohol dehydrogenase family, ADH. A class of this family is ADH3 (alcohol dehydrogenase class III) that has several known substrates and inhibitors. By using virtual screening we tried to characterize new ligands. As some ligands were already known we could incorporate this knowledge when the compound docking simulations were scored and thereby find two new substrates and two new inhibitors which were subsequently successfully tested in vitro.

    ANTR1 (anion transporter 1) is a membrane bound transporter important in the photosynthesis in plants. To be able to study the amino acid residues involved in inorganic phosphate transportation a homology model of the protein was created. Important residues were then mapped onto the structure using conservation analysis and we were in this way able to propose roles of amino acid residues involved in the transportation of inorganic phosphate. Key residues were subsequently mutated in vitro and a transportation process could be postulated.

    To conclude, we have used several molecular modelling techniques to find functional clues, interaction sites and new ligands. Furthermore, we have investigated the effect of muations on the function and structure of a multitude of disease related proteins.

     

    Delarbeten
    1. Molecular Model of Human CYP21 Based onMammalian CYP2C5: Structural Features Correlatewith Clinical Severity of Mutations CausingCongenital Adrenal Hyperplasia
    Öppna denna publikation i ny flik eller fönster >>Molecular Model of Human CYP21 Based onMammalian CYP2C5: Structural Features Correlatewith Clinical Severity of Mutations CausingCongenital Adrenal Hyperplasia
    Visa övriga...
    2006 (Engelska)Ingår i: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 20, nr 11, s. 2946-2964Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Enhanced understanding of structure-function relationshipsof human 21-hydroxylase, CYP21, is requiredto better understand the molecular causesof congenital adrenal hyperplasia. To this end, astructural model of human CYP21 was calculatedbased on the crystal structure of rabbit CYP2C5.All but two known allelic variants of missense type,a total of 60 disease-causing mutations and sixnormal variants, were analyzed using this model. Astructural explanation for the corresponding phenotypewas found for all but two mutants for whichavailable clinical data are also discrepant with invitro enzyme activity. Calculations of protein stabilityof modeled mutants were found to correlateinversely with the corresponding clinical severity.Putative structurally important residues were identifiedto be involved in heme and substrate binding,redox partner interaction, and enzyme catalysisusing docking calculations and analysis of structurallydetermined homologous cytochrome P450s(CYPs). Functional and structural consequences ofseven novel mutations, V139E, C147R, R233G,T295N, L308F, R366C, and M473I, detected inScandinavian patients with suspected congenitaladrenal hyperplasia of different severity, were predictedusing molecular modeling. Structural featuresdeduced from the models are in good correlationwith clinical severity of CYP21 mutants,which shows the applicability of a modeling approachin assessment of new CYP21 mutations.

    Ort, förlag, år, upplaga, sidor
    Stanford: The endocrin society, 2006
    Nyckelord
    Mutations, prediction, CAH, CYP21, homology model
    Nationell ämneskategori
    Bioinformatik och systembiologi
    Identifikatorer
    urn:nbn:se:liu:diva-21305 (URN)10.1210/me.2006-0172 (DOI)
    Tillgänglig från: 2009-09-30 Skapad: 2009-09-30 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Investigation and prediction of the severity of p53 mutants using parameters from structural calculations
    Öppna denna publikation i ny flik eller fönster >>Investigation and prediction of the severity of p53 mutants using parameters from structural calculations
    2009 (Engelska)Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, nr 15, s. 4142-4155Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A method has been developed to predict the effects of mutations in the p53 cancer suppressor gene. The new method uses novel parameters combined with previously established parameters. The most important parameter is the stability measure of the mutated structure calculated using molecular modelling. For each mutant, a severity score is reported, which can be used for classification into deleterious and nondeleterious. Both structural features and sequence properties are taken into account. The method has a prediction accuracy of 77% on all mutants and 88% on breast cancer mutations affecting WAF1 promoter binding. When compared with earlier methods, using the same dataset, our method clearly performs better. As a result of the severity score calculated for every mutant, valuable knowledge can be gained regarding p53, a protein that is believed to be involved in over 50% of all human cancers.

    Nyckelord
    Cancer; molecular modelling; mutations; p53; structural prediction
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-20141 (URN)10.1111/j.1742-4658.2009.07124.x (DOI)
    Tillgänglig från: 2009-08-31 Skapad: 2009-08-31 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. A structural model of human steroid 11-betahydroxylase,CYP11B1, used to predict consequences of mutations
    Öppna denna publikation i ny flik eller fönster >>A structural model of human steroid 11-betahydroxylase,CYP11B1, used to predict consequences of mutations
    2009 (Engelska)Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Abstract [en]

    A prediction method has been developed to estimate the severity of amino acid residue exchanges in human steroid 11-beta-hydroxylase, CYP11B1, due to mutations in the corresponding gene. The prediction is based both on structural and on sequence dependent parameters. The method uses two approaches; one with general molecular property weights and one with a consensus voting strategy based upon distribution of molecular properties, which does not require any training. Both methods are tested on known mutations in CYP11B1 and result in 85% prediction accuracy. The consensus voting method is then further evaluated on 9 proteins with an average of 81% prediction accuracy. A server utilizing the results from the consensus voting on CYP11B1 is provided where the user can extract information about new mutants. A similar server is also provided for mutants in human steroid 21-hydroxylase (CYP21).

    Nyckelord
    CYP11B1, steroid 11-beta-hydroxylase, molecular modeling, structural prediction, mutations
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-51118 (URN)
    Tillgänglig från: 2009-10-19 Skapad: 2009-10-19 Senast uppdaterad: 2009-10-19Bibliografiskt granskad
    4. Disruption of the GDNF Binding Site in NCAM DissociatesLigand Binding and Homophilic Cell Adhesion
    Öppna denna publikation i ny flik eller fönster >>Disruption of the GDNF Binding Site in NCAM DissociatesLigand Binding and Homophilic Cell Adhesion
    Visa övriga...
    2007 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, nr 17, s. 12734-12740Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Most plasma membrane proteins are capable of sensing multiple cell-cell and cell-ligand interactions, but the extent towhich this functional versatility is founded on their modular design is less clear. We have identified the third immunoglobulin domain of the Neural Cell Adhesion Molecule (NCAM) as the necessary and sufficient determinant for its interaction with Glial Cell Line-derived Neurotrophic Factor (GDNF). Four charged contacts were identified by molecular modeling as the main contributors to binding energy. Their mutation abolished GDNF binding to NCAM but left intact the ability of NCAM tomediate cell adhesion, indicating that the two functions are genetically separable. The GDNF-NCAM interface allows complex formation with the GDNF family receptor α1, shedding light on the molecular architecture of a multicomponent GDNF receptor.

    Ort, förlag, år, upplaga, sidor
    Bethesda, MD: American Society for Biochemistry and Molecular Biology, 2007
    Nyckelord
    homology model, protein complex, interaction interface, mutagenesis
    Nationell ämneskategori
    Bioinformatik och systembiologi
    Identifikatorer
    urn:nbn:se:liu:diva-21306 (URN)10.1074/jbc.M701588200 (DOI)
    Tillgänglig från: 2009-09-30 Skapad: 2009-09-30 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    5. Functionally Important Amino Acids in the Arabidopsis Thylakoid Phosphate Transporter: Homology Modeling and Site-directed Mutagenesis
    Öppna denna publikation i ny flik eller fönster >>Functionally Important Amino Acids in the Arabidopsis Thylakoid Phosphate Transporter: Homology Modeling and Site-directed Mutagenesis
    Visa övriga...
    2010 (Engelska)Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 49, nr 30, s. 6430-6439Artikel i tidskrift (Övrigt vetenskapligt) Published
    Abstract [en]

    The anion transporter 1 (ANTR1) from Arabidopsis thaliana, homologous to the mammalian SLC17 family, has recently been localized to the chloroplast thylakoid membrane. When expressed heterologously in Escherichia coli, ANTR1 mediates a Na+-dependent active transport of inorganic phosphate (Pi). The aim of this study was to identify amino acids involved in substrate binding/translocation by ANTR1 and in the Na+-dependence of its activity. A threedimensional structural model of ANTR1 was constructed using the crystal structure of glycerol-3-phosphate/phosphate antiporter (GlpT) from E.coli as a template. Based on this model and multiple sequence alignments, five highly conserved residues in plant ANTRs and mammalian SLC17 homologues have been selected for site-directed mutagenesis, namely Arg-120, Ser-124 and Arg-201 inside the putative translocation pathway, Arg-228 and Asp-382 exposed at the cytosolic surface of the protein. The activities of the wild type and mutant proteins have been analyzed using expression in E. coli and radioactive transport assays, and compared with bacterial cells carrying an empty plasmid. Based on Pi- and Na+-dependent kinetics, we propose that Arg-120, Arg-201 and Arg-228 are involved in binding and translocation of the substrate, Ser-124 functions as a periplasmic gate for Na+ ions, and finally Asp-382 participates in the turnover of the transporter via ionic interaction with either Arg-228 or Na+ ions. We also propose that the corresponding residues may have a similar function in other plant and mammalian SLC17 homologous transporters.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-51119 (URN)10.1021/bi100239j (DOI)
    Anmärkning
    On the day of the defence day the status of this article was ManuscriptTillgänglig från: 2009-10-19 Skapad: 2009-10-19 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    6. A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulations
    Öppna denna publikation i ny flik eller fönster >>A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulations
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Amyloidosis is the largest group among the protein misfolding diseases, and includes well known diseases such as Alzheimer’s disease and type 2 diabetes. In the latter, islet amyloid is present in the pancreas in almost all individuals. Today, more than 25 different proteins have been isolated from amyloid deposits in human. Even though these proteins differ in size, charge and sequence they all have the capacity to assemble in to fibrillar structures with inseparable morphological appearance. Therefore, it can be assumed that the fibril process is based upon principles that are general for all proteins and knowledge derived from one protein can be used for other amyloid proteins. In this paper, we study the process of amyloid formation in parts of islet amyloid polypeptide (residues 18-29 and 11-37) by analyzing mutations using three different in silico methods. Finally, we use the methods to predict the amyloidogenic properties of the native IAPP and 16 variants thereof and compare the result with in vitro measurements. Using a consensus prediction of the three methods we managed to correctly classify all but two peptides. We have also given further evidence to the importance of S28P for inhibiting amyloid fibre formation, found evidence for antiparallel stacking, and identified important regions for beta sheet stability.

    Nyckelord
    IAPP, molecular modeling, amyloid, prediction, molecular dynamics, Monte Carlo
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-51120 (URN)
    Tillgänglig från: 2009-10-19 Skapad: 2009-10-19 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
    7. Virtual screening for ligands to human alcohol dehydrogenase 3
    Öppna denna publikation i ny flik eller fönster >>Virtual screening for ligands to human alcohol dehydrogenase 3
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Alcohol dehydrogenase 3 (ADH3) has been suggested a role in nitric oxide homeostasis due to its function as a S-nitrosoglutathione (GSNO) reductase. This has requested a modulator of the ADH3 activity for control of GSNO levels. Today virtual screenings are frequently used in drug discovery to dock and rank a large number of compounds. With molecular dockings of more than 40,000 compounds into the active site pocket of human ADH3 we ranked compounds with a novel method. Six top ranked compounds that were not known to interact with ADH3 were tested in vitro, where two showed substrate activity (9-decen-1-ol and dodecyltetraglycol), two showed inhibition capacity (deoxycholic acid and doxorubicin) and two did not have any detectable effect. For the substrates, site specific interactions and calculated binding scoring energies were determined with an extended docking simulation including flexible side chains of amino acids residues. The binding scoring energies correlated well with the logarithm of the substrates kcat over Km values. Furthermore, with these computational and experimental data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs and in addition deoxycholic acids.

    Nyckelord
    Alcohol dehydrogenase, Enzyme kinetics, Molecular docking, Virtual screening
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-51121 (URN)
    Tillgänglig från: 2009-10-19 Skapad: 2009-10-19 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
  • 32.
    Carlsson, Jonas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Investigating protein variants using structural calculation techniques2012Ingår i: Homology Modeling: Methods and Protocols / [ed] Andrew J. W. Orry and Ruben Abagyan, Springer, 2012, Vol. 857, s. 313-330Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Knowledge about protein tertiary structure can guide experiments, assist in the understanding of structure-function relationships, and aid the design of new therapeutics for disease. Homology modeling is an in silico method that predicts the tertiary structure of an amino acid sequence based on a homologous experimentally determined structure. In, Homology Modeling: Methods and Protocols experts in the field describe each homology modeling step from first principles, provide case studies for challenging modeling targets and describe methods for the prediction of how other molecules such as drugs can interact with the protein. Written in the highly successful Methods in Molecular Biology series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Thorough and intuitive, Homology Modeling: Methods and Protocols guides scientists in the available homology modeling methods.

  • 33.
    Carlsson, Jonas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Soussi, Thierry
    Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Investigation and prediction of the severity of p53 mutants using parameters from structural calculations2009Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, nr 15, s. 4142-4155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method has been developed to predict the effects of mutations in the p53 cancer suppressor gene. The new method uses novel parameters combined with previously established parameters. The most important parameter is the stability measure of the mutated structure calculated using molecular modelling. For each mutant, a severity score is reported, which can be used for classification into deleterious and nondeleterious. Both structural features and sequence properties are taken into account. The method has a prediction accuracy of 77% on all mutants and 88% on breast cancer mutations affecting WAF1 promoter binding. When compared with earlier methods, using the same dataset, our method clearly performs better. As a result of the severity score calculated for every mutant, valuable knowledge can be gained regarding p53, a protein that is believed to be involved in over 50% of all human cancers.

  • 34.
    Carlsson, Jonas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Vahdat Shariatpanahi, Aida
    Schultz, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Westermark, Gunilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    A folding study on IAPP (Islet Amyloid Polypeptide) using molecular dynamics simulationsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Amyloidosis is the largest group among the protein misfolding diseases, and includes well known diseases such as Alzheimer’s disease and type 2 diabetes. In the latter, islet amyloid is present in the pancreas in almost all individuals. Today, more than 25 different proteins have been isolated from amyloid deposits in human. Even though these proteins differ in size, charge and sequence they all have the capacity to assemble in to fibrillar structures with inseparable morphological appearance. Therefore, it can be assumed that the fibril process is based upon principles that are general for all proteins and knowledge derived from one protein can be used for other amyloid proteins. In this paper, we study the process of amyloid formation in parts of islet amyloid polypeptide (residues 18-29 and 11-37) by analyzing mutations using three different in silico methods. Finally, we use the methods to predict the amyloidogenic properties of the native IAPP and 16 variants thereof and compare the result with in vitro measurements. Using a consensus prediction of the three methods we managed to correctly classify all but two peptides. We have also given further evidence to the importance of S28P for inhibiting amyloid fibre formation, found evidence for antiparallel stacking, and identified important regions for beta sheet stability.

  • 35.
    Carlsson, Jonas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Wedell, Anna
    Department of Molecular Medicine and Surgery, CMM:02, Karolinska Institutet/Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    A structural model of human steroid 11-betahydroxylase,CYP11B1, used to predict consequences of mutations2009Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    A prediction method has been developed to estimate the severity of amino acid residue exchanges in human steroid 11-beta-hydroxylase, CYP11B1, due to mutations in the corresponding gene. The prediction is based both on structural and on sequence dependent parameters. The method uses two approaches; one with general molecular property weights and one with a consensus voting strategy based upon distribution of molecular properties, which does not require any training. Both methods are tested on known mutations in CYP11B1 and result in 85% prediction accuracy. The consensus voting method is then further evaluated on 9 proteins with an average of 81% prediction accuracy. A server utilizing the results from the consensus voting on CYP11B1 is provided where the user can extract information about new mutants. A similar server is also provided for mutants in human steroid 21-hydroxylase (CYP21).

  • 36.
    Carlstrom, Karl E.
    et al.
    Karolinska Inst, Sweden.
    Ewing, Ewoud
    Karolinska Inst, Sweden.
    Granqvist, Mathias
    Karolinska Inst, Sweden.
    Gyllenberg, Alexandra
    Karolinska Inst, Sweden.
    Aeinehband, Shahin
    Karolinska Inst, Sweden.
    Enoksson, Sara Lind
    Karolinska Univ Hosp, Sweden.
    Checa, Antonio
    Karolinska Inst, Sweden.
    Badam, Tejaswi
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten. Univ Skovde, Sweden.
    Huang, Jesse
    Karolinska Inst, Sweden.
    Gomez-Cabrero, David
    Univ Publ Nevarra UPNA, Spain.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Al Nimer, Faiez
    Karolinska Inst, Sweden.
    Wheelock, Craig E.
    Karolinska Inst, Sweden.
    Kockum, Ingrid
    Karolinska Inst, Sweden.
    Olsson, Tomas
    Karolinska Inst, Sweden.
    Jagodic, Maja
    Karolinska Inst, Sweden.
    Piehl, Fredrik
    Karolinska Inst, Sweden.
    Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 3081Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

  • 37.
    Cederlund, Ella
    et al.
    Karolinska Institute.
    Hedlund, Joel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Hjelmqvist, Lars
    Karolinska Institute.
    Jonsson, Andreas
    Karolinska Institute.
    Shafqat, Jawed
    Karolinska Institute.
    Norin, Annika
    Karolinska Institute.
    Keung, Wing-Ming
    Harvard University.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Jornvall, Hans
    Karolinska Institute.
    Characterization of new medium-chain alcohol dehydrogenases adds resolution to duplications of the class I/III and the sub-class I genes2011Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 191, nr 03-janArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.

  • 38.
    Charalambidis, Georgios
    et al.
    University of Crete, Greece.
    Georgilis, Evangelos
    University of Crete, Greece; Fdn Research and Technology Hellas FORTH, Greece.
    Panda, Manas K.
    University of Crete, Greece; CSIR NIIST, India.
    Anson, Christopher E.
    Karlsruhe Institute Technology, Germany.
    Powell, Annie K.
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany.
    Doyle, Stephen
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany.
    Moss, David
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany.
    Jochum, Tobias
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany; Abcr GmbH, Germany.
    Horton, Peter N.
    University of Southampton, England.
    Coles, Simon J.
    University of Southampton, England.
    Linares, Mathieu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Beljonne, David
    University of Mons UMONS, Belgium; University of Mons UMONS, Belgium.
    Naubron, Jean-Valere
    Aix Marseille University, France.
    Conradt, Jonas
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany.
    Kalt, Heinz
    Karlsruhe Institute Technology, Germany; Karlsruhe Institute Technology, Germany.
    Mitraki, Anna
    University of Crete, Greece; Fdn Research and Technology Hellas FORTH, Greece.
    Coutsolelos, Athanassios G.
    University of Crete, Greece.
    Silviu Balaban, Teodor
    Aix Marseille University, France.
    A switchable self-assembling and disassembling chiral system based on a porphyrin-substituted phenylalanine-phenylalanine motif2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, nr 12657Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Artificial light-harvesting systems have until now not been able to self-assemble into structures with a large photon capture cross-section that upon a stimulus reversibly can switch into an inactive state. Here we describe a simple and robust FLFL-dipeptide construct to which a meso-tetraphenylporphyrin has been appended and which self-assembles to fibrils, platelets or nanospheres depending on the solvent composition. The fibrils, functioning as quenched antennas, give intense excitonic couplets in the electronic circular dichroism spectra which are mirror imaged if the unnatural FDFD-analogue is used. By slightly increasing the solvent polarity, these light-harvesting fibres disassemble to spherical structures with silent electronic circular dichroism spectra but which fluoresce. Upon further dilution with the nonpolar solvent, the intense Cotton effects are recovered, thus proving a reversible switching. A single crystal X-ray structure shows a head-to-head arrangement of porphyrins that explains both their excitonic coupling and quenched fluorescence.

  • 39.
    Chene, Jianlin
    et al.
    Univ Missouri, MO USA.
    Choe, Myong-Ho
    Univ Sci, North Korea.
    Elofsson, Arne
    Stockholm Univ, Sweden.
    Han, Kun-Sop
    Univ Sci, North Korea.
    Hoe, Jie
    Univ Missouri, MO USA.
    Maghrabi, Ali H. A.
    Univ Reading, England.
    McGuffin, Liam J.
    Univ Reading, England.
    Menendez-Hurtado, David
    Stockholm Univ, Sweden.
    Olechnovic, Klinnent
    Vilnius Univ, Lithuania.
    Schwede, Torsten
    Univ Basel, Switzerland.
    Studer, Gabriel
    Univ Basel, Switzerland; Univ Basel, Switzerland.
    Uziela, Karolis
    Stockholm Univ, Sweden.
    Venclovas, Ceslovas
    Vilnius Univ, Lithuania.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Estimation of model accuracy in CASP132019Ingår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methods to reliably estimate the accuracy of 3D models of proteins are both a fundamental part of most protein folding pipelines and important for reliable identification of the best models when multiple pipelines are used. Here, we describe the progress made from CASP12 to CASP13 in the field of estimation of model accuracy (EMA) as seen from the progress of the most successful methods in CASP13. We show small but clear progress, that is, several methods perform better than the best methods from CASP12 when tested on CASP13 EMA targets. Some progress is driven by applying deep learning and residue-residue contacts to model accuracy prediction. We show that the best EMA methods select better models than the best servers in CASP13, but that there exists a great potential to improve this further. Also, according to the evaluation criteria based on local similarities, such as lDDT and CAD, it is now clear that single model accuracy methods perform relatively better than consensus-based methods.

  • 40.
    Das, Jyotirmoy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects2019Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, nr 6, s. 589-601Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

  • 41.
    Dsouza, Raison
    et al.
    Max Planck Inst Struct and Dynam Matter, Germany.
    Cheng, Xinxin
    Max Planck Inst Struct and Dynam Matter, Germany; Univ Hamburg, Germany.
    Li, Zheng
    Max Planck Inst Struct and Dynam Matter, Germany.
    Miller, R. J. Dwayne
    Max Planck Inst Struct and Dynam Matter, Germany; Univ Hamburg, Germany; Univ Toronto, Canada.
    Kochman, Michal
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Oscillatory Photoelectron Signal of N-Methylmorpholine as a Test Case for the Algebraic-Diagrammatic Construction Method of Second Order2018Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 122, nr 50, s. 9688-9700Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivated by recent progress in the application of time-resolved photoelectron spectroscopy (TRPES) to molecular Rydberg states, we report herein a detailed assessment of the performance of the second-order algebraic diagrammatic construction (ADC(2)) method in the simulation of their TRPES spectra. As the test case, we employ the tertiary aliphatic amine N-methylmorpholine (NMM), which is notable for the fact that the signal of its 3s state exhibits long-lived oscillations along the electron binding energy axis. The relaxation process of photoexcited NMM is simulated via the Born-Oppenheimer molecular dynamics method, and the resulting TRPES spectrum is generated on the basis of ionization energies and approximate Dyson orbital norms calculated with the continuum orbital technique. On the whole, the simulated TRPES spectrum achieves satisfactory agreement with experiment, which suggests that the ADC(2) method provides a realistic description of the potential energy surfaces of the relevant excited and ionized states. In particular, the simulations reproduce the fine oscillatory structure of the signal of the 3s state, and provide evidence to the effect that it results from a coherent vibrational wavepacket evolving along the deformation modes of the six-membered ring. However, it is found that ADC(2) underestimates electron binding energies by up to a few tenths of an electronvolt. The case of NMM demonstrates the usefulness of ADC(2) as a tool to aid the interpretation of the TRPES spectra of large organic molecules.

  • 42.
    Durbeej, Bo
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wang, Jun
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Oruganti, Baswanth
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Molecular Photoswitching Aided by Excited-State Aromaticity2018Ingår i: ChemPlusChem, ISSN 2192-6506, Vol. 83, nr 11, s. 958-967Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Central to the development of optoelectronic devices is the availability of efficient synthetic molecular photoswitches, the design of which is an arena where the evolving concept of excited‐state aromaticity (ESA) is yet to make a big impact. The aim of this minireview is to illustrate the potential of this concept to become a key tool for the future design of photoswitches. The paper starts with a discussion of challenges facing the use of photoswitches for applications and continues with an account of how the ESA concept has progressed since its inception. Then, following some brief remarks on computational modeling of photoswitches and ESA, the paper describes two different approaches to improve the quantum yields and response times of switches driven by E/Z photoisomerization or photoinduced H‐atom/proton transfer reactions through simple ESA considerations. It is our hope that these approaches, verified by quantum chemical calculations and molecular dynamics simulations, will help stimulate the application of the ESA concept as a general tool for designing more efficient photoswitches and other functional molecules used in optoelectronic devices.

  • 43.
    Elfving, Eric
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Automated annotation of protein families2011Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction: The great challenge in bioinformatics is data integration. The amount of available data is always increasing and there are no common unified standards of where, or how, the data should be stored. The aim of this workis to build an automated tool to annotate the different member families within the protein superfamily of medium-chain dehydrogenases/reductases (MDR), by finding common properties among the member proteins. The goal is to increase the understanding of the MDR superfamily as well as the different member families.This will add to the amount of knowledge gained for free when a new, unannotated, protein is matched as a member to a specific MDR member family.

    Method: The different types of data available all needed different handling. Textual data was mainly compared as strings while numeric data needed some special handling such as statistical calculations. Ontological data was handled as tree nodes where ancestry between terms had to be considered. This was implemented as a plugin-based system to make the tool easy to extend with additional data sources of different types.

    Results: The biggest challenge was data incompleteness yielding little (or no) results for some families and thus decreasing the statistical significance of the results. Results show that all the human and mouse MDR members have a Pfam ADH domain (ADH_N and/or ADH_zinc_N) and takes part in an oxidation-reduction process, often with NAD or NADP as cofactor. Many of the proteins contain zinc and are expressed in liver tissue.

    Conclusions: A python based tool for automatic annotation has been created to annotate the different MDR member families. The tool is easily extendable to be used with new databases and much of the results agrees with information found in literature. The utility and necessity of this system, as well as the quality of its produced results, are expected to only increase over time, even if no additional extensions are produced, as the system itself is able to make further and more detailed inferences as more and more data become available.

  • 44.
    Elofsson, Arne
    et al.
    Stockholm Univ, Sweden.
    Joo, Keehyoung
    Korea Inst Adv Study, South Korea.
    Keasar, Chen
    Ben Gurion Univ Negev, Israel.
    Lee, Jooyoung
    Korea Inst Adv Study, South Korea.
    Maghrabi, Ali H. A.
    Univ Reading, England.
    Manavalan, Balachandran
    Korea Inst Adv Study, South Korea.
    McGuffin, Liam J.
    Univ Reading, England.
    Hurtado, David Menendez
    Stockholm Univ, Sweden.
    Mirabello, Claudio
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Pilstål, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Sidi, Tomer
    Ben Gurion Univ Negev, Israel.
    Uziela, Karolis
    Stockholm Univ, Sweden.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Methods for estimation of model accuracy in CASP122018Ingår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 86, s. 361-373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methods to reliably estimate the quality of 3D models of proteins are essential drivers for the wide adoption and serious acceptance of protein structure predictions by life scientists. In this article, the most successful groups in CASP12 describe their latest methods for estimates of model accuracy (EMA). We show that pure single model accuracy estimation methods have shown clear progress since CASP11; the 3 top methods (MESHI, ProQ3, SVMQA) all perform better than the top method of CASP11 (ProQ2). Although the pure single model accuracy estimation methods outperform quasi-single (ModFOLD6 variations) and consensus methods (Pcons, ModFOLDclust2, Pcomb-domain, and Wallner) in model selection, they are still not as good as those methods in absolute model quality estimation and predictions of local quality. Finally, we show that when using contact-based model quality measures (CAD, lDDT) the single model quality methods perform relatively better.

  • 45.
    Eriksson, Hanna
    et al.
    Karolinska University Hospital.
    Lengqvist, Johan
    Karolinska University Hospital.
    Hedlund, Joel
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Uhlen, Kristina
    GE Healthcare Biosci AB.
    Orre, Lukas M
    Karolinska University Hospital.
    Bjellqvist, Bengt
    GE Healthcare Biosci AB.
    Persson, Bengt
    Karolinska University Hospital.
    Lehtio, Janne
    Karolinska University Hospital.
    Jakobsson , Per-Johan
    Karolinska University Hospital.
    Quantitative membrane proteomics applying narrow range peptide isoelectric focusing for studies of small cell lung cancer resistance mechanisms2008Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, nr 15, s. 3008-3018Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Drug resistance is often associated with upregulation of membrane-associated drug-efflux systems, and thus global membrane proteomics methods are valuable tools in the search for novel components of drug resistance phenotypes. Herein we have compared the microsomal proteome from the lung cancer cell line H69 and its isogenic Doxorubicin-resistant subcell line H69AR. The method used includes microsome preparation, iTRAQ labeling followed by narrow range peptide IEF in an immobilized pH-gradient (IPG-IEF) and LC-MS/MS analysis. We demonstrate that the microsomal preparation and iTRAQ labeling is reproducible regarding protein content and composition. The rationale using narrow range peptide IPG-IEF separation is demonstrated by its ability to: (i) lowering the complexity of the sample by two-thirds while keeping high proteome coverage (96%), (ii) providing high separation efficiency, and (iii) allowing for peptide validation and possibly identifications of post-transcriptional modifications. After analyzing one-fifth of the IEF fractions (effective pH range of 4.0-4.5), a total of 3704 proteins were identified, among which 527 were predicted to be membrane proteins. One of the proteins found to be differentially expressed was Serca 2, a calcium pump located in the ER membrane that potentially could result in changes of apoptotic response toward Doxorubicin.

  • 46.
    Falklöf, Olle
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Durbeej, Bo
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Computational Identification of Pyrrole Ring C as the Preferred Donor for Excited-State Proton Transfer in Bacteriophytochromes2018Ingår i: ChemPhotoChem, ISSN 2367-0932, Vol. 2, nr 6, s. 453-457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The engineering of bacteriophytochrome photoreceptors into near-infrared fluorescent proteins is a promising route toward deep-tissue imaging of living cells with many challenges ahead. One key objective is to increase the fluorescence quantum yields, which are limited by competing non-radiative relaxation processes involving not only the well-known double-bond photoisomerization of the tetrapyrrole chromophore, but also a potential excited-state proton transfer from the chromophore to the protein. Motivated by the lack of mechanistic knowledge about this proton transfer, we here use hybrid quantum mechanics/molecular mechanics methods to investigate three possible scenarios for how the process is initiated. Through calculated excited-state pKa values of the chromophore inside the protein matrix of Deinococcus radiodurans bacteriophytochrome, it is found that pyrrole ring C is a much more likely donor for excited-state proton transfer than rings A and B, which are also possible donors discussed in the literature. This finding offers a starting point for establishing a strategy to strengthen the fluorescence of engineered bacteriophytochromes through biochemical inhibition of the proton transfer.

  • 47.
    Fang, Changfeng
    et al.
    Center for Optics Research and Engineering, Shandong University.
    Durbeej, Bo
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Calculation of Free-Energy Barriers with TD-DFT: A Case Study on Excited-State Proton Transfer in Indigo2019Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 123, nr 40, s. 8485-8495Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The performance of time-dependent density functional theory (TD-DFT) for the calculation of excited states of molecular systems has been the subject of many benchmark studies. Often, these studies focus on excitation energies or, more recently, excited-state equilibrium geometries. In this work, we take a different angle by instead exploring how well TD-DFT reproduces experimental free-energy barriers of a well-known photochemical reaction: the excited-state proton transfer (ESPT) in indigo. Specifically, by exploiting the possibility of using TD-DFT to locate and compute free energies of first-order saddle points in excited states, we test the performance of several popular density functionals in reproducing recently determined experimental free-energy barriers for ESPT in indigo and in an N-hexyl substituted derivative thereof. Through the calculations, it is found that all of the tested functionals perform quite well, uniformly overestimating the experimental values by 1.4–3.5 (mean error) and 2.5–5.5 kcal mol–1 (maximum error) only. Given that these errors are not larger than those typically observed when barriers for ground-state proton transfer reactions are calculated in ground-state DFT, the results highlight the potential of TD-DFT to enable accurate modeling of ESPT reactions based on free energies and explicit localization of transition states.

  • 48.
    Franco, Irene
    et al.
    Karolinska Inst, Sweden.
    Johansson, Anna
    Uppsala Univ, Sweden.
    Olsson, Karl
    Karolinska Inst, Sweden.
    Vrtacnik, Peter
    Karolinska Inst, Sweden.
    Lundin, Par
    Karolinska Inst, Sweden; Stockholm Univ, Sweden.
    Helgadottir, Hafdis T.
    Karolinska Inst, Sweden.
    Larsson, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Revechon, Gwladys
    Karolinska Inst, Sweden.
    Bosia, Carla
    IIGM, Italy; Politecn Torino, Italy.
    Pagnani, Andrea
    IIGM, Italy; Politecn Torino, Italy.
    Provero, Paolo
    Mol Biotechnol Ctr, Italy; Ist Sci San Raffaele, Italy.
    Gustafsson, Thomas
    Karolinska Inst, Sweden.
    Fischer, Helene
    Karolinska Inst, Sweden.
    Eriksson, Maria
    Karolinska Inst, Sweden.
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 49.
    Fucile, Geoffrey
    et al.
    University of Toronto.
    Garcia, Christel
    University of Toronto.
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Christendat, Dinesh
    University of Toronto.
    Structural and biochemical investigation of two Arabidopsis shikimate kinases: The heat-inducible isoform is thermostable2011Ingår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 20, nr 7, s. 1125-1136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The expression of plant shikimate kinase (SK; EC 2.7.1.71), an intermediate step in the shikimate pathway to aromatic amino acid biosynthesis, is induced under specific conditions of environmental stress and developmental requirements in an isoform-specific manner. Despite their important physiological role, experimental structures of plant SKs have not been determined and the biochemical nature of plant SK regulation is unknown. The Arabidopsis thaliana genome encodes two SKs, AtSK1 and AtSK2. We demonstrate that AtSK2 is highly unstable and becomes inactivated at 37 degrees C whereas the heat-induced isoform, AtSK1, is thermostable and fully active under identical conditions at this temperature. We determined the crystal structure of AtSK2, the first SK structure from the plant kingdom, and conducted biophysical characterizations of both AtSK1 and AtSK2 towards understanding this mechanism of thermal regulation. The crystal structure of AtSK2 is generally conserved with bacterial SKs with the addition of a putative regulatory phosphorylation motif forming part of the adenosine triphosphate binding site. The heat-induced isoform, AtSK1, forms a homodimer in solution, the formation of which facilitates its relative thermostability compared to AtSK2. In silico analyses identified AtSK1 site variants that may contribute to AtSK1 stability. Our findings suggest that AtSK1 performs a unique function under heat stress conditions where AtSK2 could become inactivated. We discuss these findings in the context of regulating metabolic flux to competing downstream pathways through SK-mediated control of steady state concentrations of shikimate.

  • 50.
    Gawel, Danuta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Serra-Musach, Jordi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Lilja, Sandra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Karlsson, Jan-Erik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Köpsén, Mattias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Jung Lee, Eun Jung
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Li, Xinxiu
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Magnusson, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Martinez, David
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Schafer, Samuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wu, Simon
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Åkesson, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases2019Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 11, artikel-id 47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

    Methods

    The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

    Results

    We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

    Conclusions

    Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

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