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Strategies to calculate water binding free energies in protein–ligand complexes

Strategies to calculate water binding free energies in protein–ligand complexes
Strategies to calculate water binding free energies in protein–ligand complexes
Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding. As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies, Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC), and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design.
1549-9596
1623-1633
Bodnarchuk, Michael S.
cb7c3390-a1e3-4e13-916c-200706d11f34
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bodnarchuk, Michael S.
cb7c3390-a1e3-4e13-916c-200706d11f34
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Bodnarchuk, Michael S., Viner, Russell, Michel, Julien and Essex, Jonathan W. (2014) Strategies to calculate water binding free energies in protein–ligand complexes. Journal of Chemical Information and Modeling, 54 (6), 1623-1633. (doi:10.1021/ci400674k).

Record type: Article

Abstract

Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding. As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies, Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC), and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design.

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e-pub ahead of print date: 31 March 2014
Published date: 23 June 2014
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 390567
URI: http://eprints.soton.ac.uk/id/eprint/390567
ISSN: 1549-9596
PURE UUID: a944ae0d-5c7f-4b17-85bc-eea79bece6ee
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 05 Apr 2016 08:05
Last modified: 19 Nov 2019 01:59

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