ras conformational switching simulating nucleotide-dependent conformational transitions with accelerated molecular dynamicsras构象转换与加速分子动力学模拟nucleotide-dependent构象的转变.pdfVIP

Ras Conformational Switching: Simulating Nucleotide- Dependent Conformational Transitions with Accelerated Molecular Dynamics Barry J. Grant1.*, Alemayehu A. Gorfe1.*, J. Andrew McCammon 1,2,3 1 Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America, 2 Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America, 3 Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America Abstract Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD) simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD) simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25–40 and 57–75) intermediate between GTP and GDP states, or distinct loop3 (46–49), loop7 (105–110), and a5 C-terminus (159–166) conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of a2 (residues 66–74) with a3-loop7 (93–110),