ArticlePLoS computational biology2018
Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling.
Article in PLoS computational biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed.
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Magnesium as a conformational gatekeeper of KRAS: Structural dynamics and therapeutic implications.Protein science : a publication of the Protein Society · 2026Article
- Crosstalk between KRAS and miRNAs in pancreatic cancer: Opportunities for its diagnosis, prognosis and therapeutic intervention (Review).International journal of oncology · 2026Review
- Article
- Inducible tag-free degradation of endogenous proteins with AlissAID and development of a photoactivable inducer.Communications biology · 2025Article
- Exploring binding and allosteric energy landscapes for the KRAS interactions with effector proteins using Markov state modeling of conformational ensembles and allosteric network modeling.Protein science : a publication of the Protein Society · 2025Review
- Article
- Distinct Molecular and Clinical Features of Specific Variants of KRAS Codon 12 in Pancreatic Adenocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Orthogonal RNA replication enables directed evolution and Darwinian adaptation in mammalian cells.Nature chemical biology · 2025Article
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRASJournal of chemical information and modeling · 2024Article
- Novel druggable space in human KRAS G13D discovered using structural bioinformatics and a P-loop targeting monoclonal antibody.Scientific reports · 2024Article
- MDFit: automated molecular simulations workflow enables high throughput assessment of ligands-protein dynamics.Journal of computer-aided molecular design · 2024Article
- Exploring KRas Protein Dynamics: An Integrated Molecular Dynamics Analysis of KRas Wild and Mutant Variants.ACS omega · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Decrypting Allostery in Membrane-Bound K-Ras4B Using ComplementaryJournal of the American Chemical Society · 2024Article
- Structural insights into the complex of oncogenic KRas4BLife science alliance · 2024Article
- Activating mutations drive human MEK1 kinase using a gear-shifting mechanism.The Biochemical journal · 2023Article
- A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.Biomolecules · 2023Article
- Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.Science advances · 2023Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of KRAS missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing the probabilities of occurrence of all KRAS G12X mutations and KRAS dynamics we show that this assumption does not hold true. Instead, our findings revealed an outstanding mutational bias. We conducted a thorough mutational analysis of KRAS G12X mutations and assessed to what extent the observed mutation frequencies follow a random distribution. Unique tissue-specific frequencies are displayed with specific mutations, especially with G12R, which cannot be explained by random probabilities. To clarify the underlying causes for the nonrandom probabilities, we conducted extensive atomistic molecular dynamics simulations (170 μs) to study the differences of G12X mutations on a molecular level. The simulations revealed an allosteric hydrophobic signaling network in KRAS, and that protein dynamics is altered among the G12X mutants and as such differs from the wild-type and is mutation-specific. The shift in long-timescale conformational dynamics was confirmed with Markov state modeling. A G12X mutation was found to modify KRAS dynamics in an allosteric way, which is especially manifested in the switch regions that are responsible for the effector protein binding. The findings provide a basis to understand better the oncogenic properties of KRAS G12X mutants and the consequences of the observed nonrandom frequencies of specific G12X mutations.
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