title: A flexible docking procedure for the exploration of peptide binding selectivity to known structures and homology models of PDZ domains.
abstract: PDZ domains are important scaffolding modules that typically bind to the C-termini of their interaction partners. Several structures of such complexes have been solved, revealing a conserved binding site in the PDZ domain and an extended conformation of the bound peptide. A compendium of information regarding PDZ complexes demonstrates that dissimilar C-terminal peptides bind to the same PDZ domain, and different PDZ domains can bind the same peptides. A detailed understanding of the PDZ-peptide recognition is needed to elucidate this complexity. To this end, we have designed a family of docking protocols for PDZ domains (termed PDZ-DocScheme) that is based on simulated annealing molecular dynamics and rotamer optimization, and is applicable to the docking of long peptides (20-40 rotatable bonds) to both known PDZ structures and to the more complicated problem of homology models of these domains. The resulting protocol reproduces the structures of PDZ complexes with peptides 4-8 amino acids long within 1-2 A from the experimental structure when the docking is performed to the original structure. If the structure of the target PDZ domain is an apo structure or a homology model, the docking protocol yields structures within 3 A in 9 out of 12 test cases. The automated docking procedure PDZ-DocScheme can serve in the generation of a structural context for validation of PDZ domain specificity from mutagenesis and ligand binding data.
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D010455:Peptides