In a previous paper, we described a novel empirical free energy function that was used to accurately predict experimental binding free energies for a diverse test set of 31 protein–protein complexes to within ≈1.0 kcal. Here, we extend that work and show that an updated version of the function can be used to (1) accurately predict native binding free energies and (2) rank crystallographic, native-like and non-native binding modes in a physically realistic manner. The modified function includes terms designed to capture some of the unfavorable interactions that characterize non-native interfaces. The function was used to calculate one-dimensional binding free energy surfaces for 21 protein complexes. In roughly 90% of the cases tested, the function was used to place native-like and crystallographic binding modes in global free energy minima. Our analysis further suggests that buried hydrogen bonds might provide the key to distinguishing native from non-native interactions. To the best of our knowledge our function is the only one of its kind, a single expression that can be used to accurately calculate native and non-native binding free energies for a large number of proteins. Given the encouraging results presented in this paper, future work will focus on improving the function and applying it to the protein–protein docking problem
Audie, Joseph, "Development and Validation of an Empirical Free Energy Function for Calculating Protein–Protein Binding Free Energy Surfaces" (2009). Chemistry Faculty Publications. Paper 8.