Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?

Förster resonance energy transfer (FRET) reactions involving ligands and aromatic amino acids can substantially impact the fluorescence properties of a protein-ligand complex, an impact intimately related to the corresponding binding mode. Structural characterization of such binding events in terms...

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Autores: Pinheiro, Silvana de Souza, Curutchet Barat, Carles E.
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/128162
Acesso em linha:https://hdl.handle.net/2445/128162
Access Level:acceso abierto
Palavra-chave:Fluorescència
Lligands (Bioquímica)
Dinàmica molecular
Transferència d'energia
Complexitat computacional
Fluorescence
Ligands (Biochemistry)
Molecular dynamics
Energy transfer
Computational complexity
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spelling Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?Pinheiro, Silvana de SouzaCurutchet Barat, Carles E.FluorescènciaLligands (Bioquímica)Dinàmica molecularTransferència d'energiaComplexitat computacionalFluorescenceLigands (Biochemistry)Molecular dynamicsEnergy transferComputational complexityFörster resonance energy transfer (FRET) reactions involving ligands and aromatic amino acids can substantially impact the fluorescence properties of a protein-ligand complex, an impact intimately related to the corresponding binding mode. Structural characterization of such binding events in terms of intermolecular distances can be done through the well-known R-6 distance-dependent Förster rate expression. However, such interpretation suffers from uncertainties underlying Förster theory in the description of the electronic coupling that promotes FRET, mostly related to the dipole-dipole orientation factor, dielectric screening effects and deviations from the ideal dipole approximation. Here, we investigate how Förster approximations impact the prediction of energy transfer dynamics in the complex between flurbiprofen and human serum albumin (HSA), as well as a model flurbiprofen-Trp dyad, in which recent observations of enantioselective fluorescence quenching has been ascribed to energy transfer from flurbiprofen to Trp. To this aim, we combine classical molecular dynamics simulations with polarizable quantum mechanics/molecular mechanics (QM/MM) calculations that allow overcoming Förster approximations. On the basis of our results, we discuss the potential of structure-based simulations in the characterization of drug-binding events through fluorescence techniques. Overall, we find an excellent agreement among theory and experiment both in terms of enantioselectivity and FRET times, thus strongly supporting the reliability of the binding modes proposed for the (S)- and (R)- enantiomers of flurbiprofen. In particular, we show that the dynamic quenching arises from a small fraction of drug bound to the secondary site of HSA at the interface between subdomains IIA and IIB, whereas the enantioselectivity arises from the larger flexibility of the (S)-flurbiprofen enantiomer in the binding pocket.American Chemical Society2019201920172019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion14 p.application/pdfhttps://hdl.handle.net/2445/128162Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1021/acs.jpcb.7b00217Journal of Physical Chemistry B, 2017, vol. 121, num. 10, p. 2265-2278https://doi.org/10.1021/acs.jpcb.7b00217(c) American Chemical Society , 2017info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1281622026-05-29T05:05:01Z
dc.title.none.fl_str_mv Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
title Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
spellingShingle Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
Pinheiro, Silvana de Souza
Fluorescència
Lligands (Bioquímica)
Dinàmica molecular
Transferència d'energia
Complexitat computacional
Fluorescence
Ligands (Biochemistry)
Molecular dynamics
Energy transfer
Computational complexity
title_short Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
title_full Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
title_fullStr Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
title_full_unstemmed Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
title_sort Can Förster Theory Describe Stereoselective Energy Transfer Dynamics in a Protein-Ligand Complex?
dc.creator.none.fl_str_mv Pinheiro, Silvana de Souza
Curutchet Barat, Carles E.
author Pinheiro, Silvana de Souza
author_facet Pinheiro, Silvana de Souza
Curutchet Barat, Carles E.
author_role author
author2 Curutchet Barat, Carles E.
author2_role author
dc.subject.none.fl_str_mv Fluorescència
Lligands (Bioquímica)
Dinàmica molecular
Transferència d'energia
Complexitat computacional
Fluorescence
Ligands (Biochemistry)
Molecular dynamics
Energy transfer
Computational complexity
topic Fluorescència
Lligands (Bioquímica)
Dinàmica molecular
Transferència d'energia
Complexitat computacional
Fluorescence
Ligands (Biochemistry)
Molecular dynamics
Energy transfer
Computational complexity
description Förster resonance energy transfer (FRET) reactions involving ligands and aromatic amino acids can substantially impact the fluorescence properties of a protein-ligand complex, an impact intimately related to the corresponding binding mode. Structural characterization of such binding events in terms of intermolecular distances can be done through the well-known R-6 distance-dependent Förster rate expression. However, such interpretation suffers from uncertainties underlying Förster theory in the description of the electronic coupling that promotes FRET, mostly related to the dipole-dipole orientation factor, dielectric screening effects and deviations from the ideal dipole approximation. Here, we investigate how Förster approximations impact the prediction of energy transfer dynamics in the complex between flurbiprofen and human serum albumin (HSA), as well as a model flurbiprofen-Trp dyad, in which recent observations of enantioselective fluorescence quenching has been ascribed to energy transfer from flurbiprofen to Trp. To this aim, we combine classical molecular dynamics simulations with polarizable quantum mechanics/molecular mechanics (QM/MM) calculations that allow overcoming Förster approximations. On the basis of our results, we discuss the potential of structure-based simulations in the characterization of drug-binding events through fluorescence techniques. Overall, we find an excellent agreement among theory and experiment both in terms of enantioselectivity and FRET times, thus strongly supporting the reliability of the binding modes proposed for the (S)- and (R)- enantiomers of flurbiprofen. In particular, we show that the dynamic quenching arises from a small fraction of drug bound to the secondary site of HSA at the interface between subdomains IIA and IIB, whereas the enantioselectivity arises from the larger flexibility of the (S)-flurbiprofen enantiomer in the binding pocket.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/128162
url https://hdl.handle.net/2445/128162
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1021/acs.jpcb.7b00217
Journal of Physical Chemistry B, 2017, vol. 121, num. 10, p. 2265-2278
https://doi.org/10.1021/acs.jpcb.7b00217
dc.rights.none.fl_str_mv (c) American Chemical Society , 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Chemical Society , 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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