Given the importance of peptide-mediated protein interactions in cellular processes, protein−peptide docking has received increasing attention. Here, we have developed a Hierarchical flexible Peptide Docking approach through fast generation and ensemble docking of peptide conformations, which is referred to as HPepDock. Tested on the LEADS-PEP benchmark data set of 53 diverse complexes with peptides of 3−12 residues, HPepDock performed significantly better than the 11 docking protocols of five small-molecule docking programs (DOCK, AutoDock, Auto-Dock Vina, Surflex, and GOLD) in predicting near-native binding conformations. HPepDock was also evaluated on the 19 bound/unbound and 10 unbound/unbound protein− peptide complexes of the Glide SP-PEP benchmark and showed an overall better performance than Glide SP-PEP+MM-GBSA and FlexPepDock in both bound and unbound docking. HPepDock is computationally efficient, and the average running time for docking a peptide is ∼15 min with the range from about 1 min for short peptides to around 40 min for long peptides.

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