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Protein-peptide interactions are crucial in many cellular functions.Nearly 40%of the protein–protein interactions are mediated by short peptides.Therefore,structural determination of the protein-peptide complexes is valuable for understanding the molecular mechanism of related biological processes and developing peptide drugs,in which molecular docking plays an important role.One grand challenge in peptide docking is how to consider the flexibility of peptides.Current protein-peptide docking algorithms generally rely on lengthy simulations to refine binding conformations or start with a few peptide conformations to consider limited flexibility.Here,to efficiently consider the peptide flexibility,we have developed a hierarchical algorithm for blind and flexible peptide docking by fast generation of peptide conformations and sequent global sampling of binding modes,which is referred to as HPEPDOCK.Instead of running lengthy simulations to refine peptide conformations,HPEPDOCK considers the peptide flexibility through an ensemble of peptide conformations generated by our fast MODPEP program.The generated peptide conformations were then globally docked against the whole protein by a modified version of Mdock.Our peptide docking algorithm was extensively evaluated on the LEADS-PEP and peptiDB test sets of protein-peptide complexes and compared with state-of-the-art protein-peptide docking algorithms(FlexPepDOCK,pepATTRACT,HADDOCK)and other protein-ligand docking programs(DOCK6,AutoDock,AutoDock Vina,Surflex,and GOLD).Overall,HPEPDOCK showed a significantly better performance than the other docking methods in both global and local peptide docking.Our HPEPDOCK is computationally efficient and consumed an average of~30 min for a global peptide docking job and~14 min for a local peptide docking job.The online service of HPEPDOCK can be accessed at http://huanglab.phys.hust.edu.cn/hpepdock/.