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Classification of water molecules in protein binding sites

Classification of water molecules in protein binding sites
Classification of water molecules in protein binding sites
Water molecules play a crucial role in mediating the interaction between a ligand and a macromolecular receptor. An understanding of the nature and role of each water molecule in the active site of a protein could greatly increase the efficiency of rational drug design approaches: if the propensity of a water molecule for displacement can be determined, then synthetic effort may be most profitably applied to the design of specific ligands with the displacement of this water molecule in mind. In this paper, a thermodynamic analysis of water molecules in the binding sites of six proteins, each complexed with a number of inhibitors, is presented. Two classes of water molecules were identified: those conserved and not displaced by any of the ligands, and those that are displaced by some ligands. The absolute binding free energies of 54 water molecules were calculated using the double decoupling method, with replica exchange thermodynamic integration in Monte Carlo simulations. It was found that conserved water molecules are on average more tightly bound than displaced water molecules. In addition, Bayesian statistics is used to calculate the probability that a particular water molecule may be displaced by an appropriately designed ligand, given the calculated binding free energy of the water molecule. This approach therefore allows the numerical assessment of whether or not a given water molecule should be targeted for displacement as part of a rational drug design strategy.
0002-7863
2577-2587
Barillari, Caterina
d239ca1a-27d4-4ac8-80d2-59e71d680c06
Taylor, Justine
90fe7323-50a1-4a1c-abdc-f367bef0330e
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Barillari, Caterina
d239ca1a-27d4-4ac8-80d2-59e71d680c06
Taylor, Justine
90fe7323-50a1-4a1c-abdc-f367bef0330e
Viner, Russell
d6d92ebc-31c4-4f0a-b655-ff291af3101c
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Barillari, Caterina, Taylor, Justine, Viner, Russell and Essex, Jonathan W. (2007) Classification of water molecules in protein binding sites. Journal of the American Chemical Society, 129 (9), 2577-2587. (doi:10.1021/ja066980q).

Record type: Article

Abstract

Water molecules play a crucial role in mediating the interaction between a ligand and a macromolecular receptor. An understanding of the nature and role of each water molecule in the active site of a protein could greatly increase the efficiency of rational drug design approaches: if the propensity of a water molecule for displacement can be determined, then synthetic effort may be most profitably applied to the design of specific ligands with the displacement of this water molecule in mind. In this paper, a thermodynamic analysis of water molecules in the binding sites of six proteins, each complexed with a number of inhibitors, is presented. Two classes of water molecules were identified: those conserved and not displaced by any of the ligands, and those that are displaced by some ligands. The absolute binding free energies of 54 water molecules were calculated using the double decoupling method, with replica exchange thermodynamic integration in Monte Carlo simulations. It was found that conserved water molecules are on average more tightly bound than displaced water molecules. In addition, Bayesian statistics is used to calculate the probability that a particular water molecule may be displaced by an appropriately designed ligand, given the calculated binding free energy of the water molecule. This approach therefore allows the numerical assessment of whether or not a given water molecule should be targeted for displacement as part of a rational drug design strategy.

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Published date: 2007

Identifiers

Local EPrints ID: 44767
URI: https://eprints.soton.ac.uk/id/eprint/44767
ISSN: 0002-7863
PURE UUID: fa71baba-7630-4dc2-ae3f-b498ff34bdd3
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 15 Mar 2007
Last modified: 15 Aug 2019 00:54

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