Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes

The NRAS-mutant subset of melanoma is one of the most aggressive and lethal types associated with poor overall survival. Unfortunately, a low understanding of the NRAS-mutant dynamic behavior has lead to the lack of clinically approved therapeutic agents able to directly target NRAS oncogenes. In th...

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Autores: Hu, Zheyao, Martí Rabassa, Jordi|||0000-0002-3721-9634
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/425634
Acceso en línea:https://hdl.handle.net/2117/425634
https://dx.doi.org/10.1039/D4NR03372H
Access Level:acceso abierto
Palabra clave:Oncogenes
NRAS oncogenes
well-tempered metadynamics
free energy surfaces
Oncogens
Àrees temàtiques de la UPC::Enginyeria química
Àrees temàtiques de la UPC::Ciències de la salut
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spelling Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapesHu, ZheyaoMartí Rabassa, Jordi|||0000-0002-3721-9634OncogenesNRAS oncogeneswell-tempered metadynamicsfree energy surfacesOncogensÀrees temàtiques de la UPC::Enginyeria químicaÀrees temàtiques de la UPC::Ciències de la salutThe NRAS-mutant subset of melanoma is one of the most aggressive and lethal types associated with poor overall survival. Unfortunately, a low understanding of the NRAS-mutant dynamic behavior has lead to the lack of clinically approved therapeutic agents able to directly target NRAS oncogenes. In this work, accurate local structures of NRAS and its mutants have been fully explored through the corresponding free energy surfaces obtained by microsecond scale well-tempered metadynamics simulations. Free energy calculations are crucial to reveal the precise mechanisms of Q61 mutations at the atomic level. Considering specific atom-atom distances and angles as appropriate reaction coordinates, we have obtained free energy surfaces revealing local and global minima together with their main transitions states, unveiling the mechanisms of abnormal NRAS activation from atomic-level and quantitatively analyzing the corresponding stable states. This will help to advance in our understanding of the basic mechanisms of NRAS mutations, offering new opportunities for the design of potential inhibitors.We are thankful for the financial support provided by the Spanish Ministry of Science, Innovation and Universities (funds MCIU/AEI/FEDER, EU). This publication is a part of the I + D + i project number PID2021-124297NB-C32, funded by MCIN/AEI/10.13039/501100011033/ and “FEDER Una manera de hacer Europa”. Zheyao Hu is a Ph.D. fellow from the Chinese Scholarship Council (grant 202006230070). J. M. thanks the Generalitat de Catalunya for the support through the grant Grup de Recerca SGR-Cat2021 Condensed, Complex and Quantum Matter Group reference 2021SGR-01411 and the Polytechnic University of Catalonia-Barcelona Tech through the funding AGRUPS. Computational resources awarded by the Barcelona Supercomputing Center-Spanish Supercomputing Network (grant BCV-2024-2-0005 “Simulation and modeling of biosystems with applications to medicine (1): drug design for the treatment of cancers of the RAS family”) are also acknowledged.Peer Reviewed20252025-01-0120252025-03-04journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/425634https://dx.doi.org/10.1039/D4NR03372Hreponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)InglésengAgencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2021-124297NB-C32 ESTUDIOS COMPUTACIONALES DE BIO-INTERFASES Y FLUIDOS MOLECULARES DE INTERES AMBIENTALAgencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PCI2023-145974-2 GRAPH NEURAL NETWORKS FOR ROBUST AI%2FML-DRIVEN NETWORK SECURITY APPLICATIONSopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/4256342026-05-27T15:37:01Z
dc.title.none.fl_str_mv Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
title Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
spellingShingle Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
Hu, Zheyao
Oncogenes
NRAS oncogenes
well-tempered metadynamics
free energy surfaces
Oncogens
Àrees temàtiques de la UPC::Enginyeria química
Àrees temàtiques de la UPC::Ciències de la salut
title_short Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
title_full Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
title_fullStr Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
title_full_unstemmed Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
title_sort Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two dimensional free energy landscapes
dc.creator.none.fl_str_mv Hu, Zheyao
Martí Rabassa, Jordi|||0000-0002-3721-9634
author Hu, Zheyao
author_facet Hu, Zheyao
Martí Rabassa, Jordi|||0000-0002-3721-9634
author_role author
author2 Martí Rabassa, Jordi|||0000-0002-3721-9634
author2_role author
dc.subject.none.fl_str_mv Oncogenes
NRAS oncogenes
well-tempered metadynamics
free energy surfaces
Oncogens
Àrees temàtiques de la UPC::Enginyeria química
Àrees temàtiques de la UPC::Ciències de la salut
topic Oncogenes
NRAS oncogenes
well-tempered metadynamics
free energy surfaces
Oncogens
Àrees temàtiques de la UPC::Enginyeria química
Àrees temàtiques de la UPC::Ciències de la salut
description The NRAS-mutant subset of melanoma is one of the most aggressive and lethal types associated with poor overall survival. Unfortunately, a low understanding of the NRAS-mutant dynamic behavior has lead to the lack of clinically approved therapeutic agents able to directly target NRAS oncogenes. In this work, accurate local structures of NRAS and its mutants have been fully explored through the corresponding free energy surfaces obtained by microsecond scale well-tempered metadynamics simulations. Free energy calculations are crucial to reveal the precise mechanisms of Q61 mutations at the atomic level. Considering specific atom-atom distances and angles as appropriate reaction coordinates, we have obtained free energy surfaces revealing local and global minima together with their main transitions states, unveiling the mechanisms of abnormal NRAS activation from atomic-level and quantitatively analyzing the corresponding stable states. This will help to advance in our understanding of the basic mechanisms of NRAS mutations, offering new opportunities for the design of potential inhibitors.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-01-01
2025
2025-03-04
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/425634
https://dx.doi.org/10.1039/D4NR03372H
url https://hdl.handle.net/2117/425634
https://dx.doi.org/10.1039/D4NR03372H
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2021-124297NB-C32 ESTUDIOS COMPUTACIONALES DE BIO-INTERFASES Y FLUIDOS MOLECULARES DE INTERES AMBIENTAL
Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PCI2023-145974-2 GRAPH NEURAL NETWORKS FOR ROBUST AI%2FML-DRIVEN NETWORK SECURITY APPLICATIONS
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
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
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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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