GroScore: Accurate Scoring of Protein–Protein Binding Poses Using Explicit-Solvent Free-Energy Calculations

Protein–protein docking algorithms promise a potential relief for the mismatch between the number of experimentally determined complex structures and the number of relevant protein interactions in an organism. To distinguish correctly from wrongly generated poses, it is necessary to score complexes according to their structural similarity to the real complex, which is usually done by computing interaction energies of some sort. Here, we explore the potential of free-energy calculations with statistical-mechanical foundation in the context of molecular dynamics (MD) simulations with explicit solvent to score a large number of complex poses. We introduce an adaptive sampling scheme which ensures that most sampling time is spent on the most promising poses. Our approach is illustrated by scoring of all targets in the CAPRI Score_set, a scoring benchmark set, and three additional CAPRI targets, together consisting of more than 22 000 poses. Our scoring scheme shows a performance that is competitive with the most successful approaches that were previously reported. All necessary scripts to run the automated scoring pipeline are available in the Supporting Information for this paper.