An unexpected way forward: towards a more accurate and rigorous protein-protein binding affinity scoring function by eliminating terms from an already simple scoring function

A fundamental and unsolved problem in biophysical chemistry is the development of a computationally simple, physically intuitive, and generally applicable method for accurately predicting and physically explaining protein–protein binding affinities from protein–protein interaction (PPI) complex coordinates. Here, we propose that the simplification of a previously described six-term PPI scoring function to a four term function results in a simple expression of all physically and statistically meaningful terms that can be used to accurately predict and explain binding affinities for a well-defined subset of PPIs that are characterized by (1) crystallographic coordinates, (2) rigid-body association, (3) normal interface size, and hydrophobicity and hydrophilicity, and (4) high quality experimental binding affinity measurements. We further propose that the four-term scoring function could be regarded as a core expression for future development into a more general PPI scoring function. Our work has clear implications for PPI modeling and structure-based drug design.