Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive R...

Autores
Musiani, Francesco; Rossetti, Giulia; Capece, Luciana; Gerger, Thomas Martin; Micheletti, Cristian; Varani, Gabriele; Carloni, Paolo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457–5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.
Fil: Musiani, Francesco. Scuola Internazionale Superiore di Studi Avanzati; Italia. Università di Bologna; Italia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Capece, Luciana. International Centre for Genetic Engineering and Biotechnology; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gerger, Thomas Martin. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Micheletti, Cristian. Scuola Internazionale Superiore di Studi Avanzati; Italia
Fil: Varani, Gabriele. University of Washington; Estados Unidos
Fil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Materia
Molecular Dynamics
Hiv
Tar
Rna
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:11336/33089
Acceder
id CONICETDig_cf6597d833ad843360b206c374bff87f
oai_identifier_str oai:ri.conicet.gov.ar:11336/33089
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNAMusiani, FrancescoRossetti, GiuliaCapece, LucianaGerger, Thomas MartinMicheletti, CristianVarani, GabrieleCarloni, PaoloMolecular DynamicsHivTarRnahttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457–5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.Fil: Musiani, Francesco. Scuola Internazionale Superiore di Studi Avanzati; Italia. Università di Bologna; Italia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; AlemaniaFil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; AlemaniaFil: Capece, Luciana. International Centre for Genetic Engineering and Biotechnology; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gerger, Thomas Martin. Helmholtz Gemeinschaft. Forschungszentrum Jülich; AlemaniaFil: Micheletti, Cristian. Scuola Internazionale Superiore di Studi Avanzati; ItaliaFil: Varani, Gabriele. University of Washington; Estados UnidosFil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; AlemaniaAmerican Chemical Society2014-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/33089Carloni, Paolo; Varani, Gabriele; Musiani, Francesco; Micheletti, Cristian; Rossetti, Giulia; Gerger, Thomas Martin; et al.; Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA; American Chemical Society; Journal of the American Chemical Society; 136; 44; 10-2014; 15631-156370002-7863CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/ja507812vinfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/ja507812vinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:46:21Zoai:ri.conicet.gov.ar:11336/33089instacron: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:34982025-11-12 09:46:21.642CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
title Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
spellingShingle Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
Musiani, Francesco
Molecular Dynamics
Hiv
Tar
Rna
title_short Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
title_full Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
title_fullStr Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
title_full_unstemmed Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
title_sort Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA
dc.creator.none.fl_str_mv Musiani, Francesco
Rossetti, Giulia
Capece, Luciana
Gerger, Thomas Martin
Micheletti, Cristian
Varani, Gabriele
Carloni, Paolo
author Musiani, Francesco
author_facet Musiani, Francesco
Rossetti, Giulia
Capece, Luciana
Gerger, Thomas Martin
Micheletti, Cristian
Varani, Gabriele
Carloni, Paolo
author_role author
author2 Rossetti, Giulia
Capece, Luciana
Gerger, Thomas Martin
Micheletti, Cristian
Varani, Gabriele
Carloni, Paolo
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Molecular Dynamics
Hiv
Tar
Rna
topic Molecular Dynamics
Hiv
Tar
Rna
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457–5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.
Fil: Musiani, Francesco. Scuola Internazionale Superiore di Studi Avanzati; Italia. Università di Bologna; Italia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Capece, Luciana. International Centre for Genetic Engineering and Biotechnology; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gerger, Thomas Martin. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Micheletti, Cristian. Scuola Internazionale Superiore di Studi Avanzati; Italia
Fil: Varani, Gabriele. University of Washington; Estados Unidos
Fil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
description The HIV-1 Tat protein and several small molecules bind to HIV-1 transactivation responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new antivirals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used toward this goal by bridging the gap between functionally relevant time scales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous molecular dynamics simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457–5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation toward characterizing the internal dynamics of TAR over the microsecond time scale. We show that the conformational fluctuations observed over this previously elusive time scale have a strong functionally oriented character in that they are primed to sustain and assist ligand binding.
publishDate 2014
dc.date.none.fl_str_mv 2014-10
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/11336/33089
Carloni, Paolo; Varani, Gabriele; Musiani, Francesco; Micheletti, Cristian; Rossetti, Giulia; Gerger, Thomas Martin; et al.; Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA; American Chemical Society; Journal of the American Chemical Society; 136; 44; 10-2014; 15631-15637
0002-7863
CONICET Digital
CONICET
url http://hdl.handle.net/11336/33089
identifier_str_mv Carloni, Paolo; Varani, Gabriele; Musiani, Francesco; Micheletti, Cristian; Rossetti, Giulia; Gerger, Thomas Martin; et al.; Molecular Dynamics Simulations Identify Time Scale of Conformational Changes Responsible for Conformational Selection in Molecular Recognition of HIV-1 Transactivation Responsive RNA; American Chemical Society; Journal of the American Chemical Society; 136; 44; 10-2014; 15631-15637
0002-7863
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/ja507812v
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/ja507812v
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 13.223955

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