Relation between the conformational heterogeneity and reaction cycle of Ras: molecular simulation of Ras.
Ras functions as a molecular switch by cycling between the active GTP-bound state and the inactive GDP-bound state. It is known experimentally that there is another GTP-bound state called state 1. We investigate the conformational changes and fluctuations arising from the difference in the coordinations between the switch regions and ligands in the GTP- and GDP-bound states using a total of 830 ns of molecular-dynamics simulations. Our results suggest that the large fluctuations among multiple conformations of switch I in state 1 owing to the absence of coordination between Thr-35 and Mg(2+) inhibit the binding of Ras to effectors. Furthermore, we elucidate the conformational heterogeneity in Ras by using principal component analysis, and propose a two-step reaction path from the GDP-bound state to the active GTP-bound state via state 1. This study suggests that state 1 plays an important role in signal transduction as an intermediate state of the nucleotide exchange process, although state 1 itself is an inactive state for signal transduction.
Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, Aichi, Japan.
Chigusa
C
Kobayashi
Shinji
S
Saito
D004789:Enzyme Activation; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D017433:Protein Structure, Secondary; D018631:ras Proteins / Q000737:chemistry* / Q000378:metabolism*
D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D018631:ras Proteins