Hierarchy of simulation models in predicting molecular recognition mechanisms from the binding energy landscapes: Structural analysis of the peptide complexes with SH2 domains

Computer simulations using the simplified energy function and simulated tem pering dynamics have accurately determined the native structure of the pYVP ML, SVLpYTAVQPNE, and SPGEpYVNIEF peptides in the complexes with SH2 domain s. Structural and equilibrium aspects of the peptide binding with SH2 domai ns have been studied by generating temperature-dependent binding free energ y landscapes. Once some native peptide SH2 domain contacts are constrained, the underlying binding free energy profile has the funnel-like shape that leads to a rapid and consistent acquisition of the native structure. The do minant native topology of the peptide-SH2 domain complexes represents an ex tended peptide conformation with strong specific interactions in the phosph otyrosine pocket and hydrophobic interactions of the peptide residues C-ter minal to the pTyr group. The topological features of the peptide-protein in terface are primarily determined by the thermodynamically stable phosphotyr osyl group. A diversity of structurally different binding orientations has been observed for the amino-terminal residues to the phosphotyrosine. The d ominant native topology for the peptide residues carboxy-terminal to the ph osphotyrosine is tolerant to flexibility in this region of the peptide-SH2 domain interface observed in equilibrium simulations. The energy landscape analysis has revealed a broad, entropically favorable topology of the nativ e binding mode for the bound peptides, which is robust to structural pertur bations. This could provide an additional positive mechanism underlying tol erance of the SH2 domains to hydrophobic conservative substitutions in the peptide specificity region. (C) 2001 Wiley-Liss, Inc.