A multilevel strategy for the exploration of the conformational flexibility of small molecules

Autores
Forti, Flavio; Cavasotto, Claudio Norberto; Orozco, Modesto; Barril, Xavier; Luque, F. Javier
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol.
Fil: Forti, Flavio. Universidad de Barcelona; España
Fil: Cavasotto, Claudio Norberto. University of Texas; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Orozco, Modesto. Institute of Research in Biomedicine Barcelona; España
Fil: Barril, Xavier. Universidad de Barcelona; España. Institució Catalana de Recerca i Estudis Avancats; España
Fil: Luque, F. Javier. Universidad de Barcelona; España
Materia
Semiempirical Methods
Conformational Flexibilty
Mining Minima
Energy Landscape
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/67817
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A multilevel strategy for the exploration of the conformational flexibility of small moleculesForti, FlavioCavasotto, Claudio NorbertoOrozco, ModestoBarril, XavierLuque, F. JavierSemiempirical MethodsConformational FlexibiltyMining MinimaEnergy Landscapehttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol.Fil: Forti, Flavio. Universidad de Barcelona; EspañaFil: Cavasotto, Claudio Norberto. University of Texas; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Orozco, Modesto. Institute of Research in Biomedicine Barcelona; EspañaFil: Barril, Xavier. Universidad de Barcelona; España. Institució Catalana de Recerca i Estudis Avancats; EspañaFil: Luque, F. Javier. Universidad de Barcelona; EspañaAmerican Chemical Society2012-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/67817Forti, Flavio; Cavasotto, Claudio Norberto; Orozco, Modesto; Barril, Xavier; Luque, F. Javier; A multilevel strategy for the exploration of the conformational flexibility of small molecules; American Chemical Society; Journal of Chemical Theory and Computation; 8; 5; 5-2012; 1808-18191549-9618CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/ct300097sinfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/ct300097sinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-01-14T12:51:45Zoai:ri.conicet.gov.ar:11336/67817instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-01-14 12:51:45.605CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A multilevel strategy for the exploration of the conformational flexibility of small molecules
title A multilevel strategy for the exploration of the conformational flexibility of small molecules
spellingShingle A multilevel strategy for the exploration of the conformational flexibility of small molecules
Forti, Flavio
Semiempirical Methods
Conformational Flexibilty
Mining Minima
Energy Landscape
title_short A multilevel strategy for the exploration of the conformational flexibility of small molecules
title_full A multilevel strategy for the exploration of the conformational flexibility of small molecules
title_fullStr A multilevel strategy for the exploration of the conformational flexibility of small molecules
title_full_unstemmed A multilevel strategy for the exploration of the conformational flexibility of small molecules
title_sort A multilevel strategy for the exploration of the conformational flexibility of small molecules
dc.creator.none.fl_str_mv Forti, Flavio
Cavasotto, Claudio Norberto
Orozco, Modesto
Barril, Xavier
Luque, F. Javier
author Forti, Flavio
author_facet Forti, Flavio
Cavasotto, Claudio Norberto
Orozco, Modesto
Barril, Xavier
Luque, F. Javier
author_role author
author2 Cavasotto, Claudio Norberto
Orozco, Modesto
Barril, Xavier
Luque, F. Javier
author2_role author
author
author
author
dc.subject.none.fl_str_mv Semiempirical Methods
Conformational Flexibilty
Mining Minima
Energy Landscape
topic Semiempirical Methods
Conformational Flexibilty
Mining Minima
Energy Landscape
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol.
Fil: Forti, Flavio. Universidad de Barcelona; España
Fil: Cavasotto, Claudio Norberto. University of Texas; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Orozco, Modesto. Institute of Research in Biomedicine Barcelona; España
Fil: Barril, Xavier. Universidad de Barcelona; España. Institució Catalana de Recerca i Estudis Avancats; España
Fil: Luque, F. Javier. Universidad de Barcelona; España
description Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol.
publishDate 2012
dc.date.none.fl_str_mv 2012-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/67817
Forti, Flavio; Cavasotto, Claudio Norberto; Orozco, Modesto; Barril, Xavier; Luque, F. Javier; A multilevel strategy for the exploration of the conformational flexibility of small molecules; American Chemical Society; Journal of Chemical Theory and Computation; 8; 5; 5-2012; 1808-1819
1549-9618
CONICET Digital
CONICET
url http://hdl.handle.net/11336/67817
identifier_str_mv Forti, Flavio; Cavasotto, Claudio Norberto; Orozco, Modesto; Barril, Xavier; Luque, F. Javier; A multilevel strategy for the exploration of the conformational flexibility of small molecules; American Chemical Society; Journal of Chemical Theory and Computation; 8; 5; 5-2012; 1808-1819
1549-9618
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/ct300097s
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/ct300097s
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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 reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.065482

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