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    On the Role of Water Models in Quantifying the Binding Free Energy of Highly Conserved Water Molecules in Proteins: The Case of Concanavalin A

    Fadda, Elisa and Woods, Robert J. (2011) On the Role of Water Models in Quantifying the Binding Free Energy of Highly Conserved Water Molecules in Proteins: The Case of Concanavalin A. Journal of Chemical Theory and Computation, 7 (10). pp. 3391-3398. ISSN 1549-9618

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    The ability of ligands to displace conserved water molecules in protein binding sites is of significant interest in drug design and is particularly pertinent in the case of glycomimetic drugs. This concept was explored in previous work [Clarke et al. J. Am. Chem. Soc. 2001, 123, 12238−12247 and Kadirvelraj et al. J. Am. Chem. Soc. 2008, 130, 16933–16942] for a highly conserved water molecule located in the binding site of the prototypic carbohydrate-binding protein Concanavalin A (Con A). A synthetic ligand was designed with the aim of displacing such water. While the synthetic ligand bound to Con A in an analogous manner to that of the natural ligand, crystallographic analysis demonstrated that it did not displace the conserved water. In order to quantify the affinity of this particular water for the Con A surface, we report here the calculated standard binding free energy for this water in both ligand-bound and free Con A, employing three popular water models: TIP3P, TIP4P, and TIP5P. Although each model was developed to perform well in simulations of bulk-phase water, the computed binding energies for the isolated water molecule displayed a high sensitivity to the model. Both molecular dynamics simulation and free energy results indicate that the choice of water model may greatly influence the characterization of surface water molecules as conserved (TIP5P) or not (TIP3P) in protein binding sites, an observation of considerable significance to rational drug design. Structural and theoretical aspects at the basis of the different behaviors are identified and discussed.

    Item Type: Article
    Keywords: Water Models; Binding Free Energy; Highly Conserved Water Molecules; Proteins; Concanavalin A;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7736
    Identification Number:
    Depositing User: Elisa Fadda
    Date Deposited: 12 Jan 2017 12:11
    Journal or Publication Title: Journal of Chemical Theory and Computation
    Publisher: American Chemical Society
    Refereed: Yes
    Funders: Science Foundation Ireland (SFI)
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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