Comprehensive Evaluation of Fourteen Docking Programs on Protein-Peptide Complexes and A New Strategy for Improving the Performance of Global Docking.

A large number of protein-protein interactions (PPIs) are mediated by the interactions between proteins and peptide segments in binding partners, and therefore determination of protein-peptide interactions (PpIs) is quite crucial to elucidate important biological processes and design peptides or peptidomimetic drugs that can modulate PPIs. Nowadays, as a powerful computation tool, molecular docking has been widely utilized to predict the binding structures of protein-peptide complexes. However, although a number of docking programs have been available, the systematic study on the assessment of their performance for PpIs has never been reported. In this study, a benchmark dataset consisting of 185 protein-peptide complexes with peptide length ranging from 5 to 20 residues was employed to evaluate the performance of fourteen docking programs, including three protein-protein docking programs (ZDOCK, FRODOCK, and HawkDock), three small molecule docking programs (GOLD, Surflex-Dock, and AutoDock Vina), and eight protein-peptide docking programs (GalaxyPepDock, MDockPeP, HPEPDOCK, CABS-dock, pepATTRACT, DINC, AutoDock CrankPep (ADCP), and HADDOCK peptide docking). A new evaluation parameter, named IL_RMSD, was proposed to measure the docking accuracy. In global docking, HPEPDOCK performs the best to the entire dataset and yields the success rates of 4.3%, 27.0% and 58.9% at the top 1, 10 and 100 levels, respectively. In local docking, overall, ADCP achieves the best predictions and reaches the success rates of 11.9%, 39.5% and 72.4% at the top 1, 10 and 100 levels, respectively. Furthermore, based on the assessment results, HAVM, a new global docking strategy that employed ADCP to optimize the conformations generated by HPEPDOCK and then re-ranked these conformations by VoroMQA (a scoring function for protein complexes) was presented, which shows significantly better performance than HPEPDOCK in our benchmark with the success rates of 9.7%, 39.5% and 65.9% at the top 1, 10, 100 levels, respectively. It is expected that our work can provide some helpful insights into the selection and development of improved docking programs for PpIs.