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...
| Autores: | ; ; ; ; ; |
|---|---|
| Tipo de documento: | Artigo |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universitat Politècnica de Catalunya (UPC) |
| Repositório: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | Inglês |
| OAI Identifier: | oai:upcommons.upc.edu:2117/365204 |
| Acesso em linha: | https://hdl.handle.net/2117/365204 https://dx.doi.org/10.1039/D0CP05471B |
| Nível de acesso: | Acesso aberto |
| Palavra-chave: | Molecular dynamics Dinàmica molecular Àrees temàtiques de la UPC::Física |
| _version_ | 1878734079256428544 |
|---|---|
| author | Privat, Cristian |
| 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 |
| author_browse | Bonet Ruiz, Jordi Granadino, Jose Manuel Privat, Cristian Pérez González, Juan Jesús|||0000-0002-0748-8147 Rubio Martínez, Jaime Tomás Belenguer, María Santos|||0000-0003-2493-0977 |
| 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 |
| collection | UPCommons. Portal del coneixement obert de la UPC |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_62d5d5fab71b63d5145e2d4e0b0f10eb |
| institution | Universitat Politècnica de Catalunya (UPC) |
| instname_str | Universitat Politècnica de Catalunya (UPC) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:upcommons.upc.edu:2117/365204 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Royal Society of Chemistry (RSC) |
| publisherStr | Royal Society of Chemistry (RSC) |
| reponame_str | UPCommons. Portal del coneixement obert de la UPC |
| spelling | Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites 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 Molecular dynamics Dinàmica molecular Àrees temàtiques de la UPC::Física 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. Peer Reviewed Royal Society of Chemistry (RSC) https://hdl.handle.net/2117/365204 https://dx.doi.org/10.1039/D0CP05471B |
| 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 | 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_short | 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 |
| topic | Molecular dynamics Dinàmica molecular Àrees temàtiques de la UPC::Física |
| topic_facet | Molecular dynamics Dinàmica molecular Àrees temàtiques de la UPC::Física |
| url | https://hdl.handle.net/2117/365204 https://dx.doi.org/10.1039/D0CP05471B |