Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.
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 sign...
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Public Library of Science (PLoS)
2009-03-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000325&type=printable |
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| author | Barry J Grant Alemayehu A Gorfe J Andrew McCammon |
| author_facet | Barry J Grant Alemayehu A Gorfe J Andrew McCammon |
| author_sort | Barry J Grant |
| collection | DOAJ |
| description | 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 alpha5 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 alpha2 (residues 66-74) with alpha3-loop7 (93-110), loop2 (26-37) with loop10 (145-151), and loop3 (46-49) with alpha5 (152-167). The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD) simulations, is a low-frequency motion intrinsic to the structure. |
| format | Article |
| id | doaj-art-3f5abb008d9b427f994db116a166b96c |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2009-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-3f5abb008d9b427f994db116a166b96c2025-08-20T02:00:55ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582009-03-0153e100032510.1371/journal.pcbi.1000325Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.Barry J GrantAlemayehu A GorfeJ Andrew McCammonRas 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 alpha5 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 alpha2 (residues 66-74) with alpha3-loop7 (93-110), loop2 (26-37) with loop10 (145-151), and loop3 (46-49) with alpha5 (152-167). The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD) simulations, is a low-frequency motion intrinsic to the structure.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000325&type=printable |
| spellingShingle | Barry J Grant Alemayehu A Gorfe J Andrew McCammon Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. PLoS Computational Biology |
| title | Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. |
| title_full | Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. |
| title_fullStr | Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. |
| title_full_unstemmed | Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. |
| title_short | Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. |
| title_sort | ras conformational switching simulating nucleotide dependent conformational transitions with accelerated molecular dynamics |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000325&type=printable |
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