A simulation-based method was developed recently that computes a free energy profile of discrete hydration sites of proteins from the distribution of water interaction energies. The method, SPAM (maps spelled in reverse), was evaluated for its ability to identify key protein-ligand interactions (or hot spots) by comparing to known structure-activity data of several targets. The simplicity and effectiveness of the approach have been demonstrated in both retrospective and prospective lead optimization examples, and also makes it possible to examine the role of discrete solvation in small molecule binding over the entire protein surface. By comparing to crystallographic evidence of small molecule binding present in RCSB for selected targets, we show that the local solvation properties calculated by SPAM are remarkably reliable on a global scale in predicting binding hot spots for small molecules. The highly interpretable characteristics of SPAM free energy profiles makes SPAM a robust computational tool for evaluating binding opportunities for a given target, especially when the knowledge about the target class is scarce.

Protein-ligand recognition: Insights from local solvation thermodynamics

248th National Meeting (2014)

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