CovPepDock

CovPepDock performs covalent flexible peptide docking with the Rosetta software suite to model and design electrophilic peptides that form covalent bonds with receptor cysteine residues.

Key Features:

• Covalent Binding Incorporation: Integrates modeling of covalent interactions between peptide electrophiles and receptor cysteine residues using covalent flexible docking.
• High Accuracy in Modeling: Retrospective benchmarks produced top-five scoring, near-native models in 89% of disulfide-bound peptide cases and 100% for electrophilic peptides.
• Design from Known Interfaces: Facilitates design of electrophilic peptide binders starting from known non-covalent binders or protein–protein interfaces.
• PDB-scale Candidate Identification: Applied to identify 7,154 potential peptide candidates within the Protein Data Bank (PDB).
• Experimental Validation Outcomes: Protocol testing on the 14-3-3σ and YAP1 phosphopeptide complex led to identification of seven selective irreversible peptide binders and crystallographic confirmation of one binding mode.

Scientific Applications:

• Therapeutic Development: Enables design of electrophilic peptide binders to target challenging or previously undruggable protein interfaces for drug discovery.
• Chemical Probing: Supports creation of irreversible peptide probes for functional interrogation of target proteins.

Methodology:

Rosetta-based covalent flexible peptide docking protocol that designs electrophilic peptide binders from known non-covalent binders or protein–protein interfaces, applied to screen the PDB for 7,154 candidate peptides, and retrospectively benchmarked with top-five, near-native model rates of 89% for disulfide-bound peptides and 100% for electrophilic peptides.