HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm

Abstract

Protein-peptide interactions are crucial in many cellular functions. Therefore, determining the structure of protein-peptide complexes is important for understanding the molecular mechanism of related biological processes and developing peptide drugs. HPEPDOCK is a novel web server for blind protein-peptide docking through a hierarchical algorithm. Instead of running lengthy simulations to refine peptide conformations, HPEPDOCK considers the peptide flexibility through an ensemble of peptide conformations generated by our MODPEP program. For blind global peptide docking, HPEPDOCK obtained a success rate of 33.3% in binding mode prediction on a benchmark of 57 unbound cases when the top 10 models were considered, compared to 21.1% for pepATTRACT server. HPEPDOCK also performed well in docking against homology models and obtained a success rate of 29.8% within top 10 predictions. For local peptide docking, HPEPDOCK achieved a high success rate of 72.6% on a benchmark of 62 unbound cases within top 10 predictions, compared to 45.2% for HADDOCK peptide protocol. Our HPEPDOCK server is computationally efficient and consumed an average of 29.8 mins for a global peptide docking job and 14.2 mins for a local peptide docking job. The HPEPDOCK web server is available at http://huanglab.phys.hust.edu.cn/hpepdock/.

Figure 1.

The workflow of HPEPDOCK web server for hierarchical flexible peptide docking that supports both local and global docking.

Figure 2.

The HPepDOCK server result page. At the top of the page is the job name or a unique job ID (1), and the files for download (2). Optional buttons on the right can control Jmol to visualize the binding model (3) on the left (4). The docking scores of the top 10 peptide models are shown on the bottom (5).

Figure 3.

The success rate (A) and average number of hits per complex (B) in binding mode predictions by HPEPDOCK and pepATTRACT server for global peptide docking on the benchmark of 57 test cases when several numbers of top predictions were considered. For each number of top predictions, from left to right are HPEPDOCK with unbound structure, HPEPDOCK with homology model, and pepATTRACT server with unbound structure of the protein, respectively. The corresponding IRMSDs of individual cases are listed in Supplementary Tables S3-S5.

Figure 4.

The success rates in binding mode predictions by HPEPDOCK server and HADDOCK peptide protocol for local peptide docking on the benchmark of 62 unbound cases when several numbers of top predictions were considered. The corresponding IRMSDs of individual cases are listed in Supplementary Table S6.

Figure 5.

The running time of HPEPDOCK server for a protein–peptide docking job through global peptide docking (A) and local peptide docking (B), where the complex No. is consistent with that in Supplementary Tables S1 and S2, respectively. The dashed lines indicate their average running times over all the cases of the benchmark. The corresponding running times of individual cases are listed in Supplementary Tables S3 and S6.

Figure 6.

Comparison between the crystal structure (green) and HPEPDOCK server prediction (magenta) for two peptide docking examples where the receptor is represented in molecular surface: (A) protein–peptide target (PDB code: 3BFW; IRMSD = 0.51 Å); (B) DNA-peptide target (PDB code: 2ZKF; IRMSD = 3.11 Å),