title: A novel empirical free energy function that explains and predicts protein-protein binding affinities.
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.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony, Brook, NY 11794, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Audie
authors.forename: Suzanne
authors.initials: S
authors.lastname: Scarlata
mesh_terms: D000818:Animals; D006801:Humans; D008432:Mathematical Computing; D008956:Models, Chemical; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins