Differential dynamics of RAS isoforms in GDP- and GTP-bound states
Abstract
RAS subfamily proteins regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Different RAS isoforms, though structurally similar, exhibit functional specificity and are associated with different types of cancers and developmental disorders. Understanding the dynamical differences between the isoforms is crucial for the design of inhibitors that can selectively target a particular malfunctioning isoform. In this study, we provide a comprehensive comparison of the dynamics of all the three RAS isoforms (HRAS, KRAS, and NRAS) using extensive molecular dynamics simulations in both the GDP- (total of 3.06 μs) and GTP-bound (total of 2.4 μs) states. We observed significant differences in the dynamics of the isoforms, which rather interestingly, varied depending on the type of the nucleotide bound and the simulation temperature. Both SwitchI (Residues 25-40) and SwitchII (Residues 59-75) differ significantly in their flexibility in the three isoforms. Furthermore, Principal Component Analysis showed that there are differences in the conformational space sampled by the GTP-bound RAS isoforms. We also identified a previously unreported pocket, which opens transiently during MD simulations, and can be targeted to regulate nucleotide exchange reaction or possibly interfere with membrane localization. Further, we present the first simulation study showing GDP destabilization in the wild-type RAS protein. The destabilization of GDP/GTP occurred only in 1/50 simulations, emphasizing the need of guanine nucleotide exchange factors (GEFs) to accelerate such an extremely unfavorable process. This observation along with the other results presented in this article further support our previously hypothesized mechanism of GEF-assisted nucleotide exchange.
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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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Recent advances in scaffold-based KRAS G12C inhibitors: SAR and biological evaluation insights
Bhattacharjee, T., Kumar, A., Singh, T. G., & Bhatia, R. (2026) · RSC Medicinal Chemistry · doi:10.1039/d6md00337k
- Authors
- Kapoor, A., & Travesset, A.
- Affiliations
- Iowa State University (US)
- Corresponding author
- Kapoor, Abhijeet
- Venue
- Proteins Structure Function and Bioinformatics
- Publisher
- Wiley
- Published
- 2015-04-22
- Volume
- 83
- Issue
- 6
- Pages
- 1091-1106
- ISSN
- 0887-3585 (ISSN-L)
- OpenAlex
- W1916470139
- Cited by
- 53
- References
- 49
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 5
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NSF (CAREER DMR-0748475)
- National Science Foundation [this work used Extreme Science and Engineering Discovery Environment (XSEDE)] (OCI-1053575)
- 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 isoforms, HRAS, KRAS, NRAS, GDP-bound state, GTP-bound state, nucleotide exchange, guanine nucleotide exchange factor, protein dynamics, conformational space, membrane localization, isoform-selective inhibitors
- MeSH terms
- Guanosine Diphosphate, Guanosine Triphosphate, Surface Properties, ras Proteins, Protein Isoforms, Static Electricity, Molecular Dynamics Simulation
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