Protein–Ligand Dissociation Rate Constant from All-Atom Simulation


Dissociation of a ligand isoniazid from a protein catalase was investigated using all-atom molecular dynamics (MD) simulations. Random acceleration MD (τ-RAMD) was used, in which a random artificial force applied to the ligand facilitates its dissociation. We have suggested a novel approach to extrapolate such obtained dissociation times to the zero-force limit assuming never before attempted universal exponential dependence of the bond strength on the applied force, allowing direct comparison with experimentally measured values. We have found that our calculated dissociation time was equal to 36.1 s with statistically significant values distributed in the interval of 0.2–72.0 s, which quantitatively matches the experimental value of 50 ± 8 s despite the extrapolation over 9 orders of magnitude in time.

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Divisions: College of Engineering & Physical Sciences > Aston Institute of Urban Technology and the Environment (ASTUTE)
College of Engineering & Physical Sciences > Systems analytics research institute (SARI)
College of Engineering & Physical Sciences
Additional Information: Funding Information: We acknowledge the use of Athena at HPC Midlands+, which was funded by the EPSRC on Grant EP/P020232/1, in this research, as part of the HPC Midlands+ consortium. V.F. expresses his gratitude to the Ministry of Education and Science of Ukraine for financial support in the project “Molecular docking for express identification of new potential drugs” (0119U002550). The collaboration was supported by the program H2020-MSCA-RISE-2018, project AMR-TB, Grant ID: 823922.
Uncontrolled Keywords: General Materials Science,Physical and Theoretical Chemistry
Publication ISSN: 1948-7185
Last Modified: 27 Jun 2024 10:58
Date Deposited: 06 Jul 2023 16:29
Full Text Link: https://www.res ... le/rs-816562/v1
Related URLs: ... jpclett.1c02952 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021-11-04
Published Online Date: 2021-10-27
Accepted Date: 2021-10-18
Authors: Maximova, Ekaterina
Postnikov, Eugene B.
Lavrova, Anastasia I.
Farafonov, Vladimir
Nerukh, Dmitry (ORCID Profile 0000-0001-9005-9919)



Version: Accepted Version

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