Probing hot spots on protein-protein interfaces with all-atom free-energysimulation

摘要

Modulation of protein-protein interactions by competitive small-molecule binding emerges as apromising avenue for drug discovery. Hot spots, i.e., amino acids with important contributions to theoverall interaction energy, provide useful targets within these interfaces. To avoid time-consumingmutagenesis experiments, computational alanine screening has been developed for the prediction ofhot spots based on existing structural information. Here we use the all-atom free-energy force fieldPFF02 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 molecularmarker of the basolateral membrane in epithelial cells, in complex with the ERBIN-binding domainof tyrosin kinase ERBB2. The results of our analysis agree with available experimental functionalassays, indicating that this approach is suitable for computational alanine screening and may help toidentify competitive peptides as starting points for the development of inhibitors of protein-proteininteractions for pharmaceutically relevant targets.