title: Ligand-induced conformational changes in ras p21: a normal mode and energy minimization analysis.
abstract: A normal mode and energy minimization of ras p21 is used to determine the flexibility of the protein and the origin of the conformational differences between GTP and GDP-bound forms. To preserve the integrity of the structures, a hydration shell of water molecules was included as part of the system. Certain low-frequency modes were found to have high involvement coefficients with the conformational transition between the GTP and GDP-bound structures; the involvement coefficients of some of the modes increase when the gamma-phosphate group is removed. Two unstable modes that appear in the GTP-bound structure upon deletion of the gamma-phosphate group were determined and shown to have dominant contributions in the regions of switch I and switch II; there was also a significant displacement of loop 1. The initial motion in these regions is predicted by the modes to be approximately perpendicular to the direction of the transition from the GTP-bound state to the GDP-bound state. The overall conformational change in the switch I and II regions involves rearrangements of the protein backbone within these regions, rather than rigid body motion. Differences in the low-frequency modes of the GTP and GDP-bound forms appear to play a role in ligand binding. A coupling between the helix alpha3 position and the deletion of the gamma-phosphate group may be involved in the interaction with GAP. The oncogenic mutation G12D leads to a global increase in the rigidity of the protein. Thus, the mutant is likely to have a higher barrier for the conformational change to the inactive form; this would slow the transition and could be related to its oncogenic properties.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Karplus
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D008024:Ligands; D008432:Mathematical Computing; D008958:Models, Molecular; D015689:Oncogene Protein p21(ras) / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D014867:Water / Q000378:metabolism
chemical_list: D008024:Ligands; D014867:Water; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D015689:Oncogene Protein p21(ras)