Theoretische Biophysik, Institut für Moleculare Biotechnologie (IMB),
Beutenbergstr.11,
D-07745 Jena, Germany
Transient association of proteins and accompanied conformational changes form the basis of cellular signal transduction processes. These protein-protein binding events are often mediated by small protein domains such as SH2 (Src homology 2) domains that recognize phosphotyrosines and flanking sequences. Complex formation leads to activation of kinase and phosphatase domains in signal proteins and further downstream signaling events. A better understanding of the basic molecular interactions involved in the complex formation and how associated conformational changes cause signal transmissions is essential for clarifying the mechanism of signal transduction.
Extended molecular dynamics (MD) simulations at room temperature on SH2 domains that are part of a receptor tyrosine kinase (lck56) and a receptor tyrosine phosphatase (SHP2) have been performed. Aim of the studies is to investigate the mechanism and energetics of specific ligand (peptide) recognition and how it affects conformational preferences that influence interactions with other signal protein domains. The MD data were analyzed in terms of atomic fluctuations averaged over the trajectories and compared to experimental results on the flexibility of the protein in the free and bound forms. 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 that may help to explain how a local ligand binding event can affect protein binding at a distant part of SH2 domains. Furthermore, a continuum solvent model was used for trajectory analysis to gain insight into the relative importance of various energetic contributions and the effect of protein structural relaxation on peptide ligand binding. Studies with different peptides were performed to investigate the sequence specificity of binding and chemical group contributions.