Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites

Diverse computational methods to support Fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy to support FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not been yet clearly overcome in the...

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Detalhes bibliográficos
Autores: Privat, Cristian, Granadino, Jose Manuel, Bonet Ruiz, Jordi, Tomás Belenguer, María Santos|||0000-0003-2493-0977, Pérez González, Juan Jesús|||0000-0002-0748-8147, Rubio Martínez, Jaime
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/365204
Acesso em linha:https://hdl.handle.net/2117/365204
https://dx.doi.org/10.1039/D0CP05471B
Access Level:acceso abierto
Palavra-chave:Molecular dynamics
Dinàmica molecular
Àrees temàtiques de la UPC::Física
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spelling Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sitesPrivat, CristianGranadino, Jose ManuelBonet Ruiz, JordiTomás Belenguer, María Santos|||0000-0003-2493-0977Pérez González, Juan Jesús|||0000-0002-0748-8147Rubio Martínez, JaimeMolecular dynamicsDinàmica molecularÀrees temàtiques de la UPC::FísicaDiverse computational methods to support Fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy to support FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not been yet clearly overcome in the framework of biomolecular simulations. In the present work, we discuss a systematic semi-automatic novel computational procedure, designed to surpass these difficulties. The method, named fragment dissolved Molecular Dynamics (fdMD) utilizes simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the targets of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing this way denaturation of the target, while simultaneously generating a database of ligandsolvated boxes that can be used in further studies. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means of trustfully discard spurious binding sites. To test our method, four Test cases of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 µs when needed. The reported results point that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. We also propose a set of descriptors to analyze the results, among which, the average MMGBSA and the average KDEEP energies emerge as the most robust ones.Peer ReviewedRoyal Society of Chemistry (RSC)20212021-01-0120222022-04-01journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/365204https://dx.doi.org/10.1039/D0CP05471Breponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/3652042026-05-27T15:37:01Z
dc.title.none.fl_str_mv Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
title Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
spellingShingle Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
Privat, Cristian
Molecular dynamics
Dinàmica molecular
Àrees temàtiques de la UPC::Física
title_short Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
title_full Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
title_fullStr Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
title_full_unstemmed Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
title_sort Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites
dc.creator.none.fl_str_mv Privat, Cristian
Granadino, Jose Manuel
Bonet Ruiz, Jordi
Tomás Belenguer, María Santos|||0000-0003-2493-0977
Pérez González, Juan Jesús|||0000-0002-0748-8147
Rubio Martínez, Jaime
author Privat, Cristian
author_facet Privat, Cristian
Granadino, Jose Manuel
Bonet Ruiz, Jordi
Tomás Belenguer, María Santos|||0000-0003-2493-0977
Pérez González, Juan Jesús|||0000-0002-0748-8147
Rubio Martínez, Jaime
author_role author
author2 Granadino, Jose Manuel
Bonet Ruiz, Jordi
Tomás Belenguer, María Santos|||0000-0003-2493-0977
Pérez González, Juan Jesús|||0000-0002-0748-8147
Rubio Martínez, Jaime
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Molecular dynamics
Dinàmica molecular
Àrees temàtiques de la UPC::Física
topic Molecular dynamics
Dinàmica molecular
Àrees temàtiques de la UPC::Física
description Diverse computational methods to support Fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy to support FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not been yet clearly overcome in the framework of biomolecular simulations. In the present work, we discuss a systematic semi-automatic novel computational procedure, designed to surpass these difficulties. The method, named fragment dissolved Molecular Dynamics (fdMD) utilizes simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the targets of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing this way denaturation of the target, while simultaneously generating a database of ligandsolvated boxes that can be used in further studies. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means of trustfully discard spurious binding sites. To test our method, four Test cases of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 µs when needed. The reported results point that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. We also propose a set of descriptors to analyze the results, among which, the average MMGBSA and the average KDEEP energies emerge as the most robust ones.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-01-01
2022
2022-04-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/365204
https://dx.doi.org/10.1039/D0CP05471B
url https://hdl.handle.net/2117/365204
https://dx.doi.org/10.1039/D0CP05471B
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry (RSC)
publisher.none.fl_str_mv Royal Society of Chemistry (RSC)
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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