Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras

K-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformation...

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Main Authors: Sezen Vatansever, Burak Erman, Zeynep H. Gümüş
Format: Article
Language:English
Published: Elsevier 2020-01-01
Series:Computational and Structural Biotechnology Journal
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Online Access:http://www.sciencedirect.com/science/article/pii/S2001037019303563
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author Sezen Vatansever
Burak Erman
Zeynep H. Gümüş
author_facet Sezen Vatansever
Burak Erman
Zeynep H. Gümüş
author_sort Sezen Vatansever
collection DOAJ
description K-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformations. Recently, we have investigated how the most frequently observed K-Ras mutation in cancer patients, G12D, changes its local dynamics and conformations (Vatansever et al., 2019). Here, we extend our analysis to study and compare the local effects of other frequently observed oncogenic mutations, G12C, G12V, G13D and Q61H. For this purpose, we have performed Molecular Dynamics (MD) simulations of each mutant when active (GTP-bound) and inactive (GDP-bound), analyzed their trajectories, and compared how each mutant changes local residue conformations, inter-protein distance distributions, local flexibility and residue pair correlated motions. Our results reveal that in the four active oncogenic mutants we have studied, the α2 helix moves closer to the C-terminal of the α3 helix. However, P-loop mutations cause α3 helix to move away from Loop7, and only G12 mutations change the local conformational state populations of the protein. Furthermore, the motions of coupled residues are mutant-specific: G12 mutations lead to new negative correlations between residue motions, while Q61H destroys them. Overall, our findings on the local conformational states and protein dynamics of oncogenic K-Ras mutants can provide insights for both mutant-selective and pan-mutant targeted inhibition efforts.
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spelling doaj.art-66dd03eefda54d57bfbe7b6d583d818a2022-12-21T22:47:07ZengElsevierComputational and Structural Biotechnology Journal2001-03702020-01-011810001011Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-RasSezen Vatansever0Burak Erman1Zeynep H. Gümüş2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Icahn Institute for Data Science and Genomic Technology, New York, NY, United StatesDepartment of Chemical and Biological Engineering, College of Engineering, Koç University, Istanbul, Turkey; Corresponding authors at: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States (Z.H. Gümüş).Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Icahn Institute for Data Science and Genomic Technology, New York, NY, United States; Corresponding authors at: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States (Z.H. Gümüş).K-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformations. Recently, we have investigated how the most frequently observed K-Ras mutation in cancer patients, G12D, changes its local dynamics and conformations (Vatansever et al., 2019). Here, we extend our analysis to study and compare the local effects of other frequently observed oncogenic mutations, G12C, G12V, G13D and Q61H. For this purpose, we have performed Molecular Dynamics (MD) simulations of each mutant when active (GTP-bound) and inactive (GDP-bound), analyzed their trajectories, and compared how each mutant changes local residue conformations, inter-protein distance distributions, local flexibility and residue pair correlated motions. Our results reveal that in the four active oncogenic mutants we have studied, the α2 helix moves closer to the C-terminal of the α3 helix. However, P-loop mutations cause α3 helix to move away from Loop7, and only G12 mutations change the local conformational state populations of the protein. Furthermore, the motions of coupled residues are mutant-specific: G12 mutations lead to new negative correlations between residue motions, while Q61H destroys them. Overall, our findings on the local conformational states and protein dynamics of oncogenic K-Ras mutants can provide insights for both mutant-selective and pan-mutant targeted inhibition efforts.http://www.sciencedirect.com/science/article/pii/S2001037019303563K-RasK-Ras mutantMolecular dynamicsLocal dynamics
spellingShingle Sezen Vatansever
Burak Erman
Zeynep H. Gümüş
Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
Computational and Structural Biotechnology Journal
K-Ras
K-Ras mutant
Molecular dynamics
Local dynamics
title Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
title_full Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
title_fullStr Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
title_full_unstemmed Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
title_short Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
title_sort comparative effects of oncogenic mutations g12c g12v g13d and q61h on local conformations and dynamics of k ras
topic K-Ras
K-Ras mutant
Molecular dynamics
Local dynamics
url http://www.sciencedirect.com/science/article/pii/S2001037019303563
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