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Toward a molecular understanding of the detection of amyloid proteins with flexible conjugated oligothiophenes
Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
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2014 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 118, no 42, 9820-9827 p.Article in journal (Refereed) Published
Abstract [en]

Molecular and electronic structures and optical absorption properties of oligothiophenes used for spectral assignment of amyloid deposits have been investigated for a family of probes known as luminescent conjugated oligothiophenes (LCOs). Theoretical absorption spectra have been determined using conformational averaging, combining classical molecular dynamics (MD) simulations with quantum mechanical/molecular mechanics (QM/MM) time-dependent density functional theory (TD-DFT) spectrum calculations. Theoretical absorption spectra are in excellent agreement with experiments, showing average errors below 5 nm for absorption maxima. To couple observed properties to molecular structures, a measure of planarity is defined, revealing a strong correlation between the transition wavelength of the first and dominating electronically excited state and dihedral rotations. It is shown that from this correlation, predictions can be made of the absorption properties of probes based only on information from MD trajectories. We show experimentally that red shifts observed in the excitation maxima of LCOs when bound to amyloid protein aggregates are also evident in absorption spectra. We predict that these red shifts are due to conformational restriction of the LCO in a protein binding pocket, causing a planarization of the conjugated backbone. On the basis of our studies of planarity, it is shown that such shifts are both possible and realistic.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014. Vol. 118, no 42, 9820-9827 p.
Keyword [en]
UV/vis absorption spectra, density functional theory, QM/MM, molecular dynamics
National Category
Theoretical Chemistry Organic Chemistry
URN: urn:nbn:se:liu:diva-109095DOI: 10.1021/jp506797jISI: 000343741100004OAI: diva2:737011

At the time for thesis presentation publication was in status: Manuscript

Funding agencies: We acknowledge financial support from the Swedish Research Council (Grant No. 621-2010-5014) as well as a grant for computing time at the National Supercomputer Centre (NSC), Sweden. M.L. thanks the Swedish e-Science Research Center (SeRC) for financial support. Our work is supported by the Swedish Foundation for Strategic Research (K.P.R.N., R.A.S.). K.P.R.N. is financed by an ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council. R.A.S. is enrolled in the doctoral program Forum Scientum. M.L. is grateful to Linkoping University for a guest professorship. Parts of this work were supported by the LUPAS project supported by the EU FP7 program.

Available from: 2014-08-11 Created: 2014-08-07 Last updated: 2016-10-06Bibliographically approved
In thesis
1. Light interactions in flexible conjugated dyes
Open this publication in new window or tab >>Light interactions in flexible conjugated dyes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis methodological developments have been made for the description of flexible conjugated dyes in room temperature spectrum calculations.

The methods in question target increased accuracy and efficiency by combining classical molecular dynamics (MD) simulations with time-dependent response theory spectrum calculations. For absorption and fluorescence spectroscopies a form of conformational averaging is used, where the final spectrum is obtained as an average of spectra calculated for geometries extracted from ground and excited state MD simulations. For infrared and Raman spectroscopies averaged spectra are calculated based on individual spectra, obtained for zero-temperature optimized molecular structures, weighted by conformational statistics from MD trajectories. Statistics for structural properties are also used in both cases to gain additional information about the systems, allowing more efficient utilization of computational resources. As it is essential that the molecular mechanics description of the system is highly accurate for methods of this nature to be effective, high quality force field parameters have been derived, describing the molecules of interest in either the MM3 or CHARMM force fields.

These methods have been employed in the study of three systems. The first is a platinum(II) actylide chromophore used in optical power limiting materials, for which a ultraviolet/visible absorption spectrum has been calculated. The second is a family of molecular probes called luminescent conjugated oligothiophenes, used to detect and characterize amyloid proteins, for which both absorption and fluorescence spectra have been calculated. Finally, infrared and Raman spectra have been calculated for a group of branched oligothiophenes used in organic solar cells.

In addition, solvation effects have been studied for conjugated poly\-eletrolytes in water, resulting in the development of two solvation models suitable for this class of molecules. The first uses a quantum meachanics/molecular mechanics (QM/MM) description, in which the solute mole\-cule is described using accurate quantum mechanical methods while the surrounding water molecules are described using point charges and polarizable point dipoles. The second discards the water entirely and removes the ionic groups of the solute. The QM/MM model provides highly accurate results while the cut-down model gives results of slightly lower quality but at a much reduced computational cost.

Finally, a study of protein-dye interactions has been performed, with the goal of explaining changes in the luminescence properties of the LCO chromophores when in the presence of amyloid proteins. Results were less than conclusive.

Place, publisher, year, edition, pages
Linköping, Sweden: Linköping University Electronic Press, 2014. 63 p.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1608
force field, molecular dynamics, QM/MM, solvation effects, absorption spectroscopy, fluorescence spectrosocopy, infrared spectroscopy, Raman spectroscopy, stokes shift, conjugated polyelectrolytes
National Category
Theoretical Chemistry
urn:nbn:se:liu:diva-109011 (URN)10.3384/diss.diva-109011 (DOI)978-91-7519-282-6 (print) (ISBN)
Public defence
2014-09-12, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:00 (English)
Available from: 2014-08-28 Created: 2014-07-26 Last updated: 2014-08-28Bibliographically approved

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