Prediction of the Water Content in Protein Binding Sites

By J. Michel, Julian Tirado-Rives, W. L. Jorgensen. 2009

177 citations recorded by the source corpus.

An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein-ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as JAWS, features “θ-water” molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more efficient than conventional free energy simulations. Testing of JAWS on five diverse examples (neuraminidase, scytalone dehydratase, major urinary protein 1, β-lactoglobulin, and COX-2) demonstrates its accuracy in locating hydration sites in comparison to results from high-resolution crystal structures. Possible applications include aid in refinement of protein crystal structures, drug lead optimization, setup of docking calculations and simulations of protein-ligand complexes.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances (2014, methodology): “Approaches following the inhomogeneous solvation theory [43] include JAWS [21], WaterMap [22], and WATMD (Novartis), but also other methods have been developed such as 3D-RISM [17] and SZMAP [20].”
Protein-ligand docking in the new millennium--a retrospective of 10 years in the field. (2013, methodology): “More challenging has been its application to more exposed binding sites, where nevertheless quite reasonable results have been obtained [102].”
Rational Approaches to Improving Selectivity in Drug Design (2012, background): “117,118 While their aim was not solely to determine the free energies of binding site water molecules, they demonstrated that incorporation of the water energetics could lead to improved reproduction of experimental binding energies when combined with their FEP implementation in the program MCPRO.”
Approaches to efficiently estimate solvation and explicit water energetics in ligand binding: the use of WaterMap (2013, unknown): “Although FEP does allow structural flexibility, Michel et al. showed that the results were sensitive to the initial water placement, and the Jorgensen lab necessarily applied their JAWS [49] to improve the water placement in the initial structures that feed FEP simulations [19].”