The distinct conformational dynamics of K-Ras and H-Ras A59G.
Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given th...
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Public Library of Science (PLoS)
2010-09-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000922&type=printable |
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| author | Suryani Lukman Barry J Grant Alemayehu A Gorfe Guy H Grant J Andrew McCammon |
| author_facet | Suryani Lukman Barry J Grant Alemayehu A Gorfe Guy H Grant J Andrew McCammon |
| author_sort | Suryani Lukman |
| collection | DOAJ |
| description | Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species. |
| format | Article |
| id | doaj-art-e000994812814932a0a75aa2e5a7ea19 |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-e000994812814932a0a75aa2e5a7ea192025-08-20T03:19:50ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582010-09-0169e100092210.1371/journal.pcbi.1000922The distinct conformational dynamics of K-Ras and H-Ras A59G.Suryani LukmanBarry J GrantAlemayehu A GorfeGuy H GrantJ Andrew McCammonRas proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000922&type=printable |
| spellingShingle | Suryani Lukman Barry J Grant Alemayehu A Gorfe Guy H Grant J Andrew McCammon The distinct conformational dynamics of K-Ras and H-Ras A59G. PLoS Computational Biology |
| title | The distinct conformational dynamics of K-Ras and H-Ras A59G. |
| title_full | The distinct conformational dynamics of K-Ras and H-Ras A59G. |
| title_fullStr | The distinct conformational dynamics of K-Ras and H-Ras A59G. |
| title_full_unstemmed | The distinct conformational dynamics of K-Ras and H-Ras A59G. |
| title_short | The distinct conformational dynamics of K-Ras and H-Ras A59G. |
| title_sort | distinct conformational dynamics of k ras and h ras a59g |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000922&type=printable |
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