title: Modelling of the complex between a 15-residue peptide from mSos2 and the N-terminal SH3 domain of Grb2 by molecular-dynamics simulation.
abstract: Under specific conditions, the complex formed by the adaptor protein Grb2 and the guanine-nucleotide exchange factor Sos2 is responsible for the activation of Ras, a low-molecular-weight GTPase involved in the control of cell proliferation and differentiation. The interaction between the N-terminal SH3 domain of the mouse Grb2 and one of its potential target sequences in the mouse, Sos2, a 15-residue peptide corresponding to residues 1264-1278, had been studied by NMR. However, the resulting data provided very limited information on the structure of the peptide and its interaction with the protein. Here, we present results from a molecular-dynamics simulation aimed at producing a realistic, atomic model for the interaction between the N-terminal SH3 domain of Grb2 and the SPLLPKLPPKTYKRE peptide from Sos2. In the simulation, the peptide adopts an extended conformation over the protein's binding surface. The proposed polyproline-type-II helicity appears only locally, and the peptide displays substantial flexibility. It is found that the peptide residues Lys10 to Tyr12 could be responsible for most of the specificity of the interaction.
authors.affiliation: Department of Chemical Engineering, Faculty of Science, University of Amsterdam, NL-1018 WV Amsterdam.
authors.forename: Sofía
authors.initials: S
authors.lastname: Calero
authors.forename: Santiago
authors.initials: S
authors.lastname: Lago
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: van Gunsteren
authors.forename: Xavier
authors.initials: X
authors.lastname: Daura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D051380:GRB2 Adaptor Protein / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D020664:Son of Sevenless Proteins / Q000737:chemistry*; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D010446:Peptide Fragments; D020664:Son of Sevenless Proteins; C116864:Sos2 protein, mouse; D014443:Tyrosine; D008239:Lysine