Computational design of D-peptide inhibitors of hepatitis delta antigen dimerization

Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis d elta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6 (1998) 821]. Multi ple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were id entified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue h elix expected to bind to the d-isomer of the target structure was selected as the template. Over 200 000 mutant sequences of this peptide were generat ed based on the MCSS results. A secondary structure prediction algorithm wa s used to screen all sequences, and in general only those that were predict ed to be highly helical were retained. Approximately 100 of these 14-mers w ere model built as d-peptides and docked with the l-isomer of the target mo nomer. Based on calculated interaction energies, predicted helicity, and in trahelical salt bridge patterns, a small number of peptides were selected a s the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results ha ve been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to di srupt it.