Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels

Autores
Alberini, Giulio; Paz, Sergio Alexis; Corradi, Beatrice; Abrams, Cameron F.; Benfenati, Fabio; Maragliano, Luca
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The recent determination of cryo-EM structures of voltage-gated sodium (Nav) channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Navpore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study the structural features of various neuronal Navchannels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the recently resolved configuration for Nav1.2. In particular, single Na+permeation events during standard MD runs suggest that the ion resides in the inner part of the Navselectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+translocation through the SF of the homology-based Nav1.2 model and the cryo-EM Nav1.2 structure, with different realizations of the DEKA filter domain. These additional simulations revealed distinct mechanisms for single and double Na+permeation through the wild-type SF, which has a charged lysine in the DEKA ring. Moreover, the configurations of the ions in the SF corresponding to the metastable states of the FESs are specific for each SF motif. Overall, the description of these mechanisms gives us new insights into ion conduction in human Navcryo-EM-based and cryo-EM configurations that could advance understanding of these systems and how they differ from potassium and bacterial Navchannels.
Fil: Alberini, Giulio. Polytechnic University of Marche; Italia
Fil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Departamento de Química Teórica y Computacional; Argentina
Fil: Corradi, Beatrice. Polytechnic University of Marche; Italia
Fil: Abrams, Cameron F.. Drexel University; Estados Unidos
Fil: Benfenati, Fabio. Polytechnic University of Marche; Italia
Fil: Maragliano, Luca. Polytechnic University of Marche; Italia
Materia
Voltage-gated channels
sodium channel
ion permation
free energy
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/226556
Acceder
id CONICETDig_7a8c19cb54ee8b0110a0ebeb687e2459
oai_identifier_str oai:ri.conicet.gov.ar:11336/226556
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium ChannelsAlberini, GiulioPaz, Sergio AlexisCorradi, BeatriceAbrams, Cameron F.Benfenati, FabioMaragliano, LucaVoltage-gated channelssodium channelion permationfree energyhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The recent determination of cryo-EM structures of voltage-gated sodium (Nav) channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Navpore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study the structural features of various neuronal Navchannels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the recently resolved configuration for Nav1.2. In particular, single Na+permeation events during standard MD runs suggest that the ion resides in the inner part of the Navselectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+translocation through the SF of the homology-based Nav1.2 model and the cryo-EM Nav1.2 structure, with different realizations of the DEKA filter domain. These additional simulations revealed distinct mechanisms for single and double Na+permeation through the wild-type SF, which has a charged lysine in the DEKA ring. Moreover, the configurations of the ions in the SF corresponding to the metastable states of the FESs are specific for each SF motif. Overall, the description of these mechanisms gives us new insights into ion conduction in human Navcryo-EM-based and cryo-EM configurations that could advance understanding of these systems and how they differ from potassium and bacterial Navchannels.Fil: Alberini, Giulio. Polytechnic University of Marche; ItaliaFil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Departamento de Química Teórica y Computacional; ArgentinaFil: Corradi, Beatrice. Polytechnic University of Marche; ItaliaFil: Abrams, Cameron F.. Drexel University; Estados UnidosFil: Benfenati, Fabio. Polytechnic University of Marche; ItaliaFil: Maragliano, Luca. Polytechnic University of Marche; ItaliaAmerican Chemical Society2023-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/226556Alberini, Giulio; Paz, Sergio Alexis; Corradi, Beatrice; Abrams, Cameron F.; Benfenati, Fabio; et al.; Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels; American Chemical Society; Journal of Chemical Theory and Computation; 19; 10; 4-2023; 2953-29721549-9618CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.jctc.2c00990info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.jctc.2c00990info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:08:56Zoai:ri.conicet.gov.ar:11336/226556instacron: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:34982025-10-22 11:08:56.94CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
title Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
spellingShingle Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
Alberini, Giulio
Voltage-gated channels
sodium channel
ion permation
free energy
title_short Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
title_full Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
title_fullStr Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
title_full_unstemmed Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
title_sort Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels
dc.creator.none.fl_str_mv Alberini, Giulio
Paz, Sergio Alexis
Corradi, Beatrice
Abrams, Cameron F.
Benfenati, Fabio
Maragliano, Luca
author Alberini, Giulio
author_facet Alberini, Giulio
Paz, Sergio Alexis
Corradi, Beatrice
Abrams, Cameron F.
Benfenati, Fabio
Maragliano, Luca
author_role author
author2 Paz, Sergio Alexis
Corradi, Beatrice
Abrams, Cameron F.
Benfenati, Fabio
Maragliano, Luca
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Voltage-gated channels
sodium channel
ion permation
free energy
topic Voltage-gated channels
sodium channel
ion permation
free energy
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The recent determination of cryo-EM structures of voltage-gated sodium (Nav) channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Navpore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study the structural features of various neuronal Navchannels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the recently resolved configuration for Nav1.2. In particular, single Na+permeation events during standard MD runs suggest that the ion resides in the inner part of the Navselectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+translocation through the SF of the homology-based Nav1.2 model and the cryo-EM Nav1.2 structure, with different realizations of the DEKA filter domain. These additional simulations revealed distinct mechanisms for single and double Na+permeation through the wild-type SF, which has a charged lysine in the DEKA ring. Moreover, the configurations of the ions in the SF corresponding to the metastable states of the FESs are specific for each SF motif. Overall, the description of these mechanisms gives us new insights into ion conduction in human Navcryo-EM-based and cryo-EM configurations that could advance understanding of these systems and how they differ from potassium and bacterial Navchannels.
Fil: Alberini, Giulio. Polytechnic University of Marche; Italia
Fil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Departamento de Química Teórica y Computacional; Argentina
Fil: Corradi, Beatrice. Polytechnic University of Marche; Italia
Fil: Abrams, Cameron F.. Drexel University; Estados Unidos
Fil: Benfenati, Fabio. Polytechnic University of Marche; Italia
Fil: Maragliano, Luca. Polytechnic University of Marche; Italia
description The recent determination of cryo-EM structures of voltage-gated sodium (Nav) channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Navpore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study the structural features of various neuronal Navchannels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the recently resolved configuration for Nav1.2. In particular, single Na+permeation events during standard MD runs suggest that the ion resides in the inner part of the Navselectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+translocation through the SF of the homology-based Nav1.2 model and the cryo-EM Nav1.2 structure, with different realizations of the DEKA filter domain. These additional simulations revealed distinct mechanisms for single and double Na+permeation through the wild-type SF, which has a charged lysine in the DEKA ring. Moreover, the configurations of the ions in the SF corresponding to the metastable states of the FESs are specific for each SF motif. Overall, the description of these mechanisms gives us new insights into ion conduction in human Navcryo-EM-based and cryo-EM configurations that could advance understanding of these systems and how they differ from potassium and bacterial Navchannels.
publishDate 2023
dc.date.none.fl_str_mv 2023-04
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/11336/226556
Alberini, Giulio; Paz, Sergio Alexis; Corradi, Beatrice; Abrams, Cameron F.; Benfenati, Fabio; et al.; Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels; American Chemical Society; Journal of Chemical Theory and Computation; 19; 10; 4-2023; 2953-2972
1549-9618
CONICET Digital
CONICET
url http://hdl.handle.net/11336/226556
identifier_str_mv Alberini, Giulio; Paz, Sergio Alexis; Corradi, Beatrice; Abrams, Cameron F.; Benfenati, Fabio; et al.; Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels; American Chemical Society; Journal of Chemical Theory and Computation; 19; 10; 4-2023; 2953-2972
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/url/https://pubs.acs.org/doi/10.1021/acs.jctc.2c00990
info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.jctc.2c00990
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/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
_version_ 1846781427089145856
score 12.982451

Publicaciones similares