AutoDock CrankPep: combining folding and docking to predict protein-peptide complexes

Motivation: Protein-peptide interactions mediate a wide variety of cellular and biological functions. Methods for predicting these interactions have garnered a lot of interest over the past few years, as witnessed by the rapidly growing number of peptide-based therapeutic molecules currently in clinical trials. The size and flexibility of peptides has shown to be challenging for existing automated docking software programs. Results: Here we present AutoDock CrankPep or ADCP in short, a novel approach to dock flexible peptides into rigid receptors. ADCP folds a peptide in the potential field created by the protein to predict the protein-peptide complex. We show that it outperforms leading peptide docking methods on two protein-peptide datasets commonly used for benchmarking docking methods: LEADS-PEP and peptiDB, comprised of peptides with up to 15 amino acids in length. Beyond these datasets, ADCP reliably docked a set of protein-peptide complexes containing peptides ranging in lengths from 16 to 20 amino acids. The robust performance of ADCP on these longer peptides enables accurate modeling of peptide-mediated protein-protein interactions and interactions with disordered proteins.