title: Probing hot spots on protein-protein interfaces with all-atom free-energy simulation.
abstract: Modulation of protein-protein interactions by competitive small-molecule binding emerges as a promising avenue for drug discovery. Hot spots, i.e., amino acids with important contributions to the overall interaction energy, provide useful targets within these interfaces. To avoid time-consuming mutagenesis experiments, computational alanine screening has been developed for the prediction of hot spots based on existing structural information. Here we use the all-atom free-energy force field PFF02 to identify important amino acid residues in the complexes of the chemokine interleukin-8 (CXCL8) and an N-terminal peptide of its cognate receptor CXCR1, and of ERBIN, a molecular marker of the basolateral membrane in epithelial cells, in complex with the ERBIN-binding domain of tyrosin kinase ERBB2. The results of our analysis agree with available experimental functional assays, indicating that this approach is suitable for computational alanine screening and may help to identify competitive peptides as starting points for the development of inhibitors of protein-protein interactions for pharmaceutically relevant targets.
authors.affiliation: Forschungszentrum Karlsruhe GmbH, Institut für Nanotechnologie, Postfach 3640, D-76021 Karlsruhe, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Meliciani
authors.forename: Konstantin
authors.initials: K
authors.lastname: Klenin
authors.forename: Timo
authors.initials: T
authors.lastname: Strunk
authors.forename: Katja
authors.initials: K
authors.lastname: Schmitz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wenzel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry; D003198:Computer Simulation; D004847:Epithelial Cells / Q000737:chemistry; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry*; D023062:Receptors, Interleukin-8A / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D016209:Interleukin-8; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D023062:Receptors, Interleukin-8A; C413364:ERBIN protein, human