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Sensitivity of binding free energy calculations to initial protein crystal structure

Sensitivity of binding free energy calculations to initial protein crystal structure
Sensitivity of binding free energy calculations to initial protein crystal structure
Binding free energy calculations using alchemical free energy (AFE) methods are widely considered to be the most rigorous tool in the computational drug discovery arsenal. Despite this, the calculations suffer from accuracy, precision, and reproducibility issues. In this publication, we perform a high-throughput study of more than a thousand AFE calculations, utilizing over 220 μs of total sampling time, on three different protein systems to investigate the impact of the initial crystal structure on the resulting binding free energy values. We also consider the influence of equilibration time and discover that the initial crystal structure can have a significant effect on free energy values obtained at short timescales that can manifest itself as a free energy difference of more than 1 kcal/mol. At longer timescales, these differences are largely overtaken by important rare events, such as torsional ligand motions, typically resulting in a much higher uncertainty in the obtained values. This work emphasizes the importance of rare event sampling and long-timescale dynamics in free energy calculations even for routinely performed alchemical perturbations. We conclude that an optimal protocol should not only concentrate computational resources on achieving convergence in the alchemical coupling parameter (λ) space but also on longer simulations and multiple repeats.
free energy, ligands, crystal structure, electron correlation, computer simulations
1549-9618
Suruzhon, Miroslav
4ea4dd8b-0a98-4598-9eaa-756d943b5dca
Bodnarchuk, Michael S.
cb7c3390-a1e3-4e13-916c-200706d11f34
Ciancetta, Antonella
992e4150-4131-4adc-9e00-d7d415583ea5
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Wall, Ian D.
059fa7bb-bde0-457f-8ba3-7e31cf72d3f1
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Suruzhon, Miroslav
4ea4dd8b-0a98-4598-9eaa-756d943b5dca
Bodnarchuk, Michael S.
cb7c3390-a1e3-4e13-916c-200706d11f34
Ciancetta, Antonella
992e4150-4131-4adc-9e00-d7d415583ea5
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Wall, Ian D.
059fa7bb-bde0-457f-8ba3-7e31cf72d3f1
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Suruzhon, Miroslav, Bodnarchuk, Michael S., Ciancetta, Antonella, Viner, Russell, Wall, Ian D. and Essex, Jonathan W. (2021) Sensitivity of binding free energy calculations to initial protein crystal structure. Journal of Chemical Theory and Computation. (doi:10.1021/acs.jctc.0c00972).

Record type: Article

Abstract

Binding free energy calculations using alchemical free energy (AFE) methods are widely considered to be the most rigorous tool in the computational drug discovery arsenal. Despite this, the calculations suffer from accuracy, precision, and reproducibility issues. In this publication, we perform a high-throughput study of more than a thousand AFE calculations, utilizing over 220 μs of total sampling time, on three different protein systems to investigate the impact of the initial crystal structure on the resulting binding free energy values. We also consider the influence of equilibration time and discover that the initial crystal structure can have a significant effect on free energy values obtained at short timescales that can manifest itself as a free energy difference of more than 1 kcal/mol. At longer timescales, these differences are largely overtaken by important rare events, such as torsional ligand motions, typically resulting in a much higher uncertainty in the obtained values. This work emphasizes the importance of rare event sampling and long-timescale dynamics in free energy calculations even for routinely performed alchemical perturbations. We conclude that an optimal protocol should not only concentrate computational resources on achieving convergence in the alchemical coupling parameter (λ) space but also on longer simulations and multiple repeats.

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More information

Accepted/In Press date: 29 December 2020
e-pub ahead of print date: 3 February 2021
Keywords: free energy, ligands, crystal structure, electron correlation, computer simulations

Identifiers

Local EPrints ID: 447009
URI: http://eprints.soton.ac.uk/id/eprint/447009
ISSN: 1549-9618
PURE UUID: b95bfcb8-a8d0-4834-99e7-3a5e7a72ae29
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 01 Mar 2021 17:34
Last modified: 02 Mar 2021 02:33

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