Soft docking an L and a D peptide to an anticholera toxin antibody using internal coordinate mechanics

Background: The tremendous increase in sequential and structural informatio n is a challenge for computer-assisted modelling to predict the binding mod es of interacting biomolecules. One important area is: the structural under standing of protein-peptide interactions, information that is increasingly important for the design of biologically active compounds. Results: We predicted the three-dimensional structure of a complex between the monoclonal antibody TE33 and its cholera-toxin-derived peptide epitope VPGSQHID. Using the internal coordinate mechanics (ICM) method of flexible docking, the bound conformation of the initially extended peptide epitope t o the antibody crystal or modelled structure reproduced the known binding c onformation to a root mean square deviation of between 1.9 Angstrom and 3.1 Angstrom. The predicted complexes are in good agreement with binding data obtained from substitutional analyses in which each epitope residue is repl aced by all other amino acids. Furthermore, a de novo prediction of the rec ently discovered TE33-binding D peptide dwGsqhydp (single-letter amino acid code where D amino acids are represented by lower-case letters) explains r esults obtained from binding studies with 172 peptide analogues. Conclusions: Despite the difficulties arising from the huge conformational space of a peptide, this approach allowed the prediction of the correct bin ding orientation and the majority of essential binding features of a peptid e-antibody complex.