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Biophys Chem. 2007 Sep;129(2-3):198-211. Epub 2007 Jun 7.

A novel empirical free energy function that explains and predicts protein-protein binding affinities.

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1
Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony, Brook, NY 11794, USA.

Abstract

A free energy function can be defined as a mathematical expression that relates macroscopic free energy changes to microscopic or molecular properties. Free energy functions can be used to explain and predict the affinity of a ligand for a protein and to score and discriminate between native and non-native binding modes. However, there is a natural tension between developing a function fast enough to solve the scoring problem but rigorous enough to explain and predict binding affinities. Here, we present a novel, physics-based free energy function that is computationally inexpensive, yet explanatory and predictive. The function results from a derivation that assumes the cost of polar desolvation can be ignored and that includes a unique and implicit treatment of interfacial water-bridged interactions. The function was parameterized on an internally consistent, high quality training set giving R2=0.97 and Q2=0.91. We used the function to blindly and successfully predict binding affinities for a diverse test set of 31 wild-type protein-protein and protein-peptide complexes (R2=0.79, rmsd=1.2 kcal mol(-1)). The function performed very well in direct comparison with a recently described knowledge-based potential and the function appears to be transferable. Our results indicate that our function is well suited for solving a wide range of protein/peptide design and discovery problems.

PMID:
17600612
DOI:
10.1016/j.bpc.2007.05.021
[Indexed for MEDLINE]
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