Protein–Ligand Dissociation Rate Constant from All-Atom Simulation

Ekaterina Maximova; Eugene B. Postnikov; Anastasia I. Lavrova; Vladimir Farafonov; Dmitry Nerukh

doi:10.1021/acs.jpclett.1c02952

Protein–Ligand Dissociation Rate Constant from All-Atom Simulation

Ekaterina Maximova, Eugene B. Postnikov, Anastasia I. Lavrova, Vladimir Farafonov, Dmitry Nerukh

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	10631–10636
Number of pages	6
Journal	Journal of Physical Chemistry Letters
Volume	12
Issue number	43
Early online date	27 Oct 2021
DOIs	https://doi.org/10.1021/acs.jpclett.1c02952
Publication status	Published - 4 Nov 2021

Bibliographical note

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.

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10.1021/acs.jpclett.1c02952

Protein-ligand Dissociation Rate
This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry Letters, copyright © 2021 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jpclett.1c02952
Accepted author manuscript, 1.39 MB

https://www.researchsquare.com/article/rs-816562/v1Licence: CC BY 3.0

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title = "Protein–Ligand Dissociation Rate Constant from All-Atom Simulation",

abstract = "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.",

author = "Ekaterina Maximova and Postnikov, {Eugene B.} and Lavrova, {Anastasia I.} and Vladimir Farafonov and Dmitry Nerukh",

note = "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. ",

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AU - Postnikov, Eugene B.

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AU - Farafonov, Vladimir

AU - Nerukh, Dmitry

N1 - 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.

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N2 - 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.

AB - 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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JO - Journal of Physical Chemistry Letters

JF - Journal of Physical Chemistry Letters

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ER -

Protein–Ligand Dissociation Rate Constant from All-Atom Simulation

Abstract

Bibliographical note

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