ECCB 2002 Poster sorted by: Author | Number

Next | Previous poster (in order of the view you have selected)
Title: Molecular dynamics simulations on the free and complexed SHP2-SH2 domain
P176
Wieligmann, Karin; Zacharias, Martin

wieligma@imb-jena.de
Theoretische Biophysik, Institut für Moleculare Biotechnologie (IMB),
Beutenbergstr.11, D-07745 Jena, Germany

Signal transduction events are often mediated by tyrosine phosphatases that are members of the Src family. These are highly conserved signaling proteins, in which a catalytic phosphatase domain (PTP) is preceded by two SH2 (Src homology) domains. Binding of a phosphotyrosyl (pY) peptide to the N-terminal SH2 domain causes dissociation and thereby activation of the PTP domain. The crystal structures of the isolated SH2 domain in peptide-bound and peptide-free form differ from the conformation observerd in the crystal structure of the intact molecule. Therefor the crystal structures themself are insufficient to explain differences in ligand dependent binding behaviour to the PTP domain.

To get a better understanding of the allosteric mechanism that leads to domain dissociation upon pY-peptide binding comparative molecular dynamics (MD) simulations on the N-SH2 domain in ligand-bound, ligand-free and PTP-bound state have been performed. The MD data were analyzed in terms of atomic fluctuations averaged over the trajectories. A principal component analysis of the trajectories was carried out with the aim to investigate the effect of binding on large concerted motions in SH2 domains.Significant differences in its dynamic behavior that arise from the state of association of the protein were found. This may help to explain how a local ligand binding event can affect protein binding at a distant part of SH2 domains.