Computational Mapping of Anchoring Spots on Protein Surfaces

Abstract

Protein–protein and protein–peptide interactions are often controlled by few strong contacts that involve hot spot residues. Computational detection of such contacts, termed here anchoring spots, is important for understanding recognition processes and for predicting interactions; it is an essential step in designing interaction interfaces and therapeutic agents. We describe ANCHORS MAP, an algorithm for computational mapping of amino acid side chains on protein surfaces. The algorithm consists of two stages: A geometry based stage (LSMdet), in which sub-pockets adequate for binding single side chains are detected and amino acid probes are scattered near them, and an energy based stage in which optimal positions of the probes are determined through repeated energy minimization and clustering of nearby poses and their Δ G are calculated. ANCHORS MAP employs a new function for Δ G calculations, which is specifically designed for the context of protein-protein recognition by introducing a correction in the electrostatic energy term that compensates for the dielectric shielding exerted by a hypothetical protein bound to the probe. The algorithm successfully detects known anchoring sites and accurately positions the probes. The calculated ΔG rank high the correct anchoring spots in maps produced for unbound proteins. We find that Arg, Trp, Glu and Tyr, which are favorite hot spot residues, are also more selective of their binding environment. The usefulness of anchoring spots mapping is demonstrated by detecting the binding surfaces in the protein-protein complex barnase/barstar and the protein-peptide complex kinase/PKI, and by identifying phenylalanine anchoring sites on the surface of the nuclear transporter NTF2, C-terminus anchors on PDZ domains and phenol anchors on thermolysin. Finally, we discuss the role of anchoring spots in molecular recognition processes.