A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics

Bak is a pro-apoptotic protein, member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation by death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the a...

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Autores: Vila-Julia, Guillem, Perez, Juan J., Rubio Martínez, Jaime
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/200147
Acceso en línea:https://hdl.handle.net/2445/200147
Access Level:acceso abierto
Palabra clave:Simulació per ordinador
Pèptids
Proteïnes
Computer simulation
Peptides
Proteins
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spelling A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamicsVila-Julia, GuillemPerez, Juan J.Rubio Martínez, JaimeSimulació per ordinadorPèptidsProteïnesComputer simulationPeptidesProteinsBak is a pro-apoptotic protein, member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation by death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumours where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, place where both pro and anti-apoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of alter Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites, has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.American Chemical Society2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/200147Articles publicats en revistes (Ciència dels Materials i Química Física)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1021/acs.jcim.3c00397Journal of Chemical Information and Modeling, 2023, vol. 63, num. 11, p. 3544-3556https://doi.org/10.1021/acs.jcim.3c00397(c) American Chemical Society , 2023info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2001472026-05-27T06:46:51Z
dc.title.none.fl_str_mv A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
title A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
spellingShingle A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
Vila-Julia, Guillem
Simulació per ordinador
Pèptids
Proteïnes
Computer simulation
Peptides
Proteins
title_short A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
title_full A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
title_fullStr A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
title_full_unstemmed A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
title_sort A Step forward toward selective activation/inhibition of Bak, a pro-apoptotic member of the Bcl-2 protein family: discovery of new prospective allosteric sites using molecular dynamics
dc.creator.none.fl_str_mv Vila-Julia, Guillem
Perez, Juan J.
Rubio Martínez, Jaime
author Vila-Julia, Guillem
author_facet Vila-Julia, Guillem
Perez, Juan J.
Rubio Martínez, Jaime
author_role author
author2 Perez, Juan J.
Rubio Martínez, Jaime
author2_role author
author
dc.subject.none.fl_str_mv Simulació per ordinador
Pèptids
Proteïnes
Computer simulation
Peptides
Proteins
topic Simulació per ordinador
Pèptids
Proteïnes
Computer simulation
Peptides
Proteins
description Bak is a pro-apoptotic protein, member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation by death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumours where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, place where both pro and anti-apoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of alter Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites, has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.
publishDate 2023
dc.date.none.fl_str_mv 2023
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/2445/200147
url https://hdl.handle.net/2445/200147
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.jcim.3c00397
Journal of Chemical Information and Modeling, 2023, vol. 63, num. 11, p. 3544-3556
https://doi.org/10.1021/acs.jcim.3c00397
dc.rights.none.fl_str_mv (c) American Chemical Society , 2023
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Chemical Society , 2023
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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 (Ciència dels Materials i Química Física)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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