Combining Solvent Thermodynamic Profiles with Functionality Maps of the Hsp90 Binding Site to Predict the Displacement of Water Molecules

Kamran Haider,David J Huggins

doi:10.1021/ci4003409

Abstract

Intermolecular interactions in the aqueous phase must compete with the interactions between the two binding partners and their solvating water molecules. In biological systems, water molecules in protein binding sites cluster at well-defined hydration sites and can form strong hydrogen-bonding interactions with backbone and side-chain atoms. Displacement of such water molecules is only favorable when the ligand can form strong compensating hydrogen bonds. Conversely, water molecules in hydrophobic regions of protein binding sites make only weak interactions, and the requirements for favorable displacement are less stringent. The propensity of water molecules for displacement can be identified using inhomogeneous fluid solvation theory (IFST), a statistical mechanical method that decomposes the solvation free energy of a solute into the contributions from different spatial regions and identifies potential binding hotspots. In this study, we employed IFST to study the displacement of water molecules from the ATP binding site of Hsp90, using a test set of 103 ligands. The predicted contribution of a hydration site to the hydration free energy was found to correlate well with the observed displacement. Additionally, we investigated if this correlation could be improved by using the energetic scores of favorable probe groups binding at the location of hydration sites, derived from a multiple copy simultaneous search (MCSS) method. The probe binding scores were not highly predictive of the observed displacement and did not improve the predictivity when used in combination with IFST-based hydration free energies. The results show that IFST alone can be used to reliably predict the observed displacement of water molecules in Hsp90. However, MCSS can augment IFST calculations by suggesting which functional groups should be used to replace highly displaceable water molecules. Such an approach could be very useful in improving the hit-to-lead process for new drug targets.

Highlights

Water molecules are a key component of biological systems and act as ordered structural elements at binding interfaces.[1]
We have combined inhomogeneous fluid solvation theory (IFST) calculations of solvent thermodynamics with multiple copy simultaneous search (MCSS) probe analysis to predict the observed displacement of water molecules from protein hydration sites on Hsp[90] and the best type of functional moiety to replace them, in the context of small molecule ligand design
IFST calculations of the hydration site free energies yielded a moderate correlation with the observed displacement, an encouraging result given the number and variety of ligands considered

Summary

Introduction

Water molecules are a key component of biological systems and act as ordered structural elements at binding interfaces.[1]. Numerous examples of water-mediated protein−ligand interactions are known, including peptide binding in tyrosine kinase (Src),[2] binding of inhibitors to proteases,[3] and carbohydratebinding proteins.[4] The consideration of individual water molecules in ligand design hinges on an accurate assessment of opposing thermodynamic contributions This includes the entropic gain of displacing a highly ordered water molecule and the enthalpic loss of breaking water−protein hydrogen bonds.[5] assessing the role of individual water molecules at the binding interface is a complex problem, as highlighted by the prediction that there is no direct correlation between the free energy of water molecules in the binding site and the affinity of bound ligands.[6]

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Results

Conclusion