Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants: Interaction Patterns in Ras Oncogenic Mutants
Open accessAbstract
Despite years of study, the structural or dynamical basis for the differential reactivity and oncogenicity of Ras isoforms and mutants remains unclear. In this study, we investigated the effects of amino acid variations on the structure and dynamics of wild type and oncogenic mutants G12D, G12V, and G13D of H- and K-Ras proteins. Based on data from µs-scale molecular dynamics simulations, we show that the overall structure of the proteins remains similar but there are important differences in dynamics and interaction networks. We identified differences in residue interaction patterns around the canonical switch and distal loop regions, and persistent sodium ion binding near the GTP particularly in the G13D mutants. Our results also suggest that different Ras variants have distinct local structural features and interactions with the GTP, variations that have the potential to affect GTP release and hydrolysis. Furthermore, we found that H-Ras proteins and particularly the G12V and G13D variants are significantly more flexible than their K-Ras counterparts. Finally, while most of the simulated proteins sampled the effector-interacting state 2 conformational state, G12V and G13D H-Ras adopted an open switch state 1 conformation that is defective in effector interaction. These differences have implications for Ras GTPase activity, effector or exchange factor binding, dimerization and membrane interaction. Proteins 2017; 85:1618-1632. © 2017 Wiley Periodicals, Inc.
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Previous molecular dynamics simulation studies of KRAS at microsecond timescales had total simulation times in the range of 1-8 μs, which is likely not sufficient to unravel long-time dynamics associated with slow conformational changes.
“The total simulation times of these studies were in the range of 1–8 μs, which is reasonable but likely not sufficient to unravel long-time dynamics associated with slow conformational changes.”
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- Authors
- Sayyed-Ahmad, A., Prakash, P., & Gorfe, A. A.
- Affiliations
- Department of Integrative Biology and Pharmacology; University of Texas Health Science Center at Houston; Houston Texas 77030
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Gorfe, Alemayehu A.
- Venue
- Proteins Structure Function and Bioinformatics
- Publisher
- Wiley
- Published
- 2017-05-31
- Volume
- 85
- Issue
- 9
- Pages
- 1618-1632
- ISSN
- 0887-3585 (ISSN-L)
- PMC
- PMC5568977
- OpenAlex
- W2612664817
- Cited by
- 54
- References
- 94
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 9 · 2019: 9 · 2018: 5 · 2017: 1
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM100078)
- Cancer Prevention and Research Institute of Texas (DP150093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Ras GTPase, H-Ras, KRAS, G12D, G12V, P-loop, protein dynamics, residue interaction networks, switch regions, sodium ion binding, GTP binding, GTPase activity, effector binding, protein flexibility, membrane interactions
- MeSH terms
- Amino Acid Sequence, Guanosine Triphosphate, Humans, Ligands, Mutation, Neoplasms, Protein Binding, Protein Conformation, Proto-Oncogene Proteins p21(ras), ras Proteins, Mutant Proteins
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