BRD4: Quantum mechanical protein-ligand binding free energies using the full-protein DFT-based QM-PBSA method
BRD4: Quantum mechanical protein-ligand binding free energies using the full-protein DFT-based QM-PBSA method
Fully quantum mechanical approaches to calculating protein–ligand free energies of binding have the potential to reduce empiricism and explicitly account for all physical interactions responsible for protein–ligand binding. In this study, we show a realistic test of the linear-scaling DFT-based QM-PBSA method to estimate quantum mechanical protein–ligand binding free energies for a set of ligands binding to the pharmaceutical drug-target bromodomain containing protein 4 (BRD4). We show that quantum mechanical QM-PBSA is a significant improvement over traditional MM-PBSA in terms of accuracy against experiment and ligand rank ordering and that the quantum and classical binding energies are converged to a similar degree. We test the interaction entropy and normal mode entropy correction terms to QM- and MM-PBSA.
25240-25249
Gundelach, Lennart
a091b82a-bae9-416e-b3dd-c046eda60a38
Fox, Thomas
a3570e56-2aad-43f3-b68a-bead17e8f728
Skylaris, Chris-Kriton
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Tautermann, Christofer
a7f51084-c3a6-4f4e-8adc-1dace6a9c801
6 October 2022
Gundelach, Lennart
a091b82a-bae9-416e-b3dd-c046eda60a38
Fox, Thomas
a3570e56-2aad-43f3-b68a-bead17e8f728
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Tautermann, Christofer
a7f51084-c3a6-4f4e-8adc-1dace6a9c801
Gundelach, Lennart, Fox, Thomas, Skylaris, Chris-Kriton and Tautermann, Christofer
(2022)
BRD4: Quantum mechanical protein-ligand binding free energies using the full-protein DFT-based QM-PBSA method.
Physical Chemistry Chemical Physics, 24 (41), .
(doi:10.1039/D2CP03705J).
Abstract
Fully quantum mechanical approaches to calculating protein–ligand free energies of binding have the potential to reduce empiricism and explicitly account for all physical interactions responsible for protein–ligand binding. In this study, we show a realistic test of the linear-scaling DFT-based QM-PBSA method to estimate quantum mechanical protein–ligand binding free energies for a set of ligands binding to the pharmaceutical drug-target bromodomain containing protein 4 (BRD4). We show that quantum mechanical QM-PBSA is a significant improvement over traditional MM-PBSA in terms of accuracy against experiment and ligand rank ordering and that the quantum and classical binding energies are converged to a similar degree. We test the interaction entropy and normal mode entropy correction terms to QM- and MM-PBSA.
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d2cp03705j
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Accepted/In Press date: 6 October 2022
e-pub ahead of print date: 6 October 2022
Published date: 6 October 2022
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Funding Information:
The authors acknowledge the use of the IRIDIS 5 High Performance Computing Facility, and associated support services at the University of Southampton, in the completion of this work. We are grateful for computational support from the UK Materials and Molecular Modelling Hub, which is partially funded by EPSRC (grant reference number EP/T022213/1). We are also grateful for access to the ARCHER2 national supercomputer which was obtained via the UKCP consortium, funded by EPSRC (grant reference number EP/P022030/1). L. G. would also like to thank the CDT for Theory and Modelling the Chemical Sciences (EPSRC grant reference number EP/L015722/1) and Boehringer Ingelheim for financial support in the form of a PhD studentship.
Publisher Copyright:
© 2022 The Royal Society of Chemistry.
Identifiers
Local EPrints ID: 471378
URI: http://eprints.soton.ac.uk/id/eprint/471378
ISSN: 1463-9076
PURE UUID: e7fd841d-4ce0-4f04-8cd8-20a00822084d
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Date deposited: 04 Nov 2022 17:36
Last modified: 06 Jun 2024 01:44
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Author:
Lennart Gundelach
Author:
Thomas Fox
Author:
Christofer Tautermann
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