Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches

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dc.authoridvan der Spoel, David/0000-0002-7659-8526
dc.authoridGapsys, Vytautas/0000-0002-6761-7780
dc.authoridYildirim, Ahmet/0000-0003-1495-0288
dc.contributor.authorGapsys, Vytautas
dc.contributor.authorYildirim, Ahmet
dc.contributor.authorAldeghi, Matteo
dc.contributor.authorKhalak, Yuriy
dc.contributor.authorvan der Spoel, David
dc.contributor.authorde Groot, Bert L.
dc.date.accessioned2024-12-24T19:27:59Z
dc.date.available2024-12-24T19:27:59Z
dc.date.issued2021
dc.departmentSiirt Üniversitesi
dc.description.abstractMolecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein-ligand binding affinity.
dc.description.sponsorshipSwedish research council [2013-5947]; High Performance Computing Center North in Umea, Sweden [SNIC2017-12-41]; BioExcel CoE - European Union [H2020-INFRAEDI-02-2018-823830]; Alexander von Humboldt Foundation; Vlaams Agentschap Innoveren & Ondernemen (VLAIO) [HBC.2018.2295]
dc.description.sponsorshipThe Swedish research council is acknowledged for financial support to D.v.d.S. (grant 2013-5947) and for a grant of computer time (SNIC2017-12-41) through the High Performance Computing Center North in Umea, Sweden, and the PDC Center for High Performance Computing at the Royal Institute of Technology, Stockholm, Sweden. V.G. and B.L.d.G. were supported by the BioExcel CoE (http://www.bioexcel.eu), a project funded by the European Union (Contract H2020-INFRAEDI-02-2018-823830). M.A. was supported by a Postdoctoral Research Fellowship of the Alexander von Humboldt Foundation. Y.K. was supported by the Vlaams Agentschap Innoveren & Ondernemen (VLAIO) project number HBC.2018.2295, Dynamics for Molecular Design (DynaMoDe).
dc.identifier.doi10.1038/s42004-021-00498-y
dc.identifier.issn2399-3669
dc.identifier.issue1
dc.identifier.pmid36697634
dc.identifier.scopus2-s2.0-85105786740
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1038/s42004-021-00498-y
dc.identifier.urihttps://hdl.handle.net/20.500.12604/6869
dc.identifier.volume4
dc.identifier.wosWOS:000656226900004
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherNature Research
dc.relation.ispartofCommunications Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241222
dc.titleAccurate absolute free energies for ligand-protein binding based on non-equilibrium approaches
dc.typeArticle

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