Quantifying the standard binding free energy of highly conserved water molecules in proteins binding sites: how important is the choice of water model?

Elisa Fadda
National University of Ireland, Galway

Abstract: 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 a prototypic carbohydrate-binding plant lectin Concanavalin A (ConA). A synthetic ligand was designed with the aim of displacing such water. While the synthetic ligand binds ConA in an analogous manner as 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 ConA surface, we report here the calculated standard binding free energy for the water in both ligand-bound and free ConA. All calculations were run with two water models, i.e. TIP3P and TIP5P. Our results show an unexpectedly high sensitivity of the binding energy to the water model used. The results show that the choice of water model may greatly influence the characterization of surface water molecules as displaceable or conserved in protein binding sites, an observation of considerable significance to rational
drug design.

Presentation (PowerPoint File)

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