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Ligand binding free energies with adaptive water networks: two-dimensional grand canonical alchemical perturbations

Ligand binding free energies with adaptive water networks: two-dimensional grand canonical alchemical perturbations
Ligand binding free energies with adaptive water networks: two-dimensional grand canonical alchemical perturbations

Computational methods to calculate ligand binding affinities are increasing in popularity, due to improvements in simulation algorithms, computational resources, and easy-to-use software. However, issues can arise in relative ligand binding free energy simulations if the ligands considered have different active site water networks, as simulations are typically performed with a predetermined number of water molecules (fixed N ensembles) in preassigned locations. If an alchemical perturbation is attempted where the change should result in a different active site water network, the water molecules may not be able to adapt appropriately within the time scales of the simulations - particularly if the active site is occluded. By combining the grand canonical ensemble (μVT) to sample active site water molecules, with conventional alchemical free energy methods, the water network is able to dynamically adapt to the changing ligand. We refer to this approach as grand canonical alchemical perturbation (GCAP). In this work we demonstrate GCAP for two systems; Scytalone Dehydratase (SD) and Adenosine A2A receptor. For both systems, GCAP is shown to perform well at reproducing experimental binding affinities. Calculating the relative binding affinities with a nalve, conventional attempt to solvate the active site illustrates how poor results can be if proper consideration of water molecules in occluded pockets is neglected. GCAP results are shown to be consistent with time-consuming double decoupling simulations. In addition, by obtaining the free energy surface for ligand perturbations, as a function of both the free energy coupling parameter and water chemical potential, it is possible to directly deconvolute the binding energetics in terms of protein-ligand direct interactions and protein binding site hydration.

1549-9618
6586-6597
Bruce Macdonald, Hannah E.
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Cave-Ayland, Christopher
0fac5a8c-02ac-4b42-857f-4b0288c9b125
Ross, Gregory A.
113a6add-41b2-4ccc-9ab9-73fb52d728c5
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bruce Macdonald, Hannah E.
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Cave-Ayland, Christopher
0fac5a8c-02ac-4b42-857f-4b0288c9b125
Ross, Gregory A.
113a6add-41b2-4ccc-9ab9-73fb52d728c5
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Bruce Macdonald, Hannah E., Cave-Ayland, Christopher, Ross, Gregory A. and Essex, Jonathan W. (2018) Ligand binding free energies with adaptive water networks: two-dimensional grand canonical alchemical perturbations. Journal of Chemical Theory and Computation, 14 (12), 6586-6597. (doi:10.1021/acs.jctc.8b00614).

Record type: Article

Abstract

Computational methods to calculate ligand binding affinities are increasing in popularity, due to improvements in simulation algorithms, computational resources, and easy-to-use software. However, issues can arise in relative ligand binding free energy simulations if the ligands considered have different active site water networks, as simulations are typically performed with a predetermined number of water molecules (fixed N ensembles) in preassigned locations. If an alchemical perturbation is attempted where the change should result in a different active site water network, the water molecules may not be able to adapt appropriately within the time scales of the simulations - particularly if the active site is occluded. By combining the grand canonical ensemble (μVT) to sample active site water molecules, with conventional alchemical free energy methods, the water network is able to dynamically adapt to the changing ligand. We refer to this approach as grand canonical alchemical perturbation (GCAP). In this work we demonstrate GCAP for two systems; Scytalone Dehydratase (SD) and Adenosine A2A receptor. For both systems, GCAP is shown to perform well at reproducing experimental binding affinities. Calculating the relative binding affinities with a nalve, conventional attempt to solvate the active site illustrates how poor results can be if proper consideration of water molecules in occluded pockets is neglected. GCAP results are shown to be consistent with time-consuming double decoupling simulations. In addition, by obtaining the free energy surface for ligand perturbations, as a function of both the free energy coupling parameter and water chemical potential, it is possible to directly deconvolute the binding energetics in terms of protein-ligand direct interactions and protein binding site hydration.

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More information

Accepted/In Press date: 1 November 2018
e-pub ahead of print date: 19 November 2018
Published date: 11 December 2018

Identifiers

Local EPrints ID: 428423
URI: http://eprints.soton.ac.uk/id/eprint/428423
ISSN: 1549-9618
PURE UUID: cc1ef725-2e81-47b5-9fa6-ebc751cc03d8
ORCID for Christopher Cave-Ayland: ORCID iD orcid.org/0000-0003-0942-8030
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 22 Feb 2019 17:31
Last modified: 17 Dec 2019 02:00

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Contributors

Author: Hannah E. Bruce Macdonald
Author: Christopher Cave-Ayland ORCID iD
Author: Gregory A. Ross

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