ArticleJournal of the American Chemical Society2023
Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.
Article in Journal of the American Chemical Society, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Investigating the effects of missense mutations on the dual Ras/Rap activation mechanism of SYNGAP1 using molecular modelling.Journal of structural biology: X · 2026Article
- How Functional Variants Reconfigure the Rac2 Conformational Landscape.The journal of physical chemistry. B · 2026Article
- Nature Counts to Three: Universal Mg-Pinch Motif Polarizes the Cleaved Bond in NTP-Processing Enzymes.Journal of the American Chemical Society · 2026Article
- How Functional Variants Reconfigure the Rac2 Conformational Landscape.bioRxiv : the preprint server for biology · 2026Article
- Systematically Improvable and Locality Accelerated Enzymatic Reactivity Modeling: Toward Chemical Accuracy at Affordable Cost.Journal of chemical theory and computation · 2026Article
- Article
- Molecular Mechanism of ATP Hydrolysis Catalyzed by p97: A QM/MM Study.Journal of chemical theory and computation · 2025Article
- Hybrid DFT Quality Thermochemistry and Environment Effects at GGA Cost via Local Quantum Embedding.Journal of chemical theory and computation · 2025Article
- Mechanism for Nucleotidyl Transfer in LINE-1 ORF2p Revealed by QM/MM Simulations.International journal of molecular sciences · 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
- Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.Protein science : a publication of the Protein Society · 2025Article
- Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning.Molecules (Basel, Switzerland) · 2024Article
- Systematic QM/MM Study for PredictingJournal of chemical theory and computation · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
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5 authors.
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Abstract
Ras GTPases play a crucial role in cell signaling pathways. Mutations of the Ras gene occur in about one third of cancerous cell lines and are often associated with detrimental clinical prognosis. Hot spot residues Gly12, Gly13, and Gln61 cover 97% of oncogenic mutations, which impair the enzymatic activity in Ras. Using QM/MM free energy calculations, we present a two-step mechanism for the GTP hydrolysis catalyzed by the wild-type Ras.GAP complex. We found that the deprotonation of the catalytic water takes place via the Gln61 as a transient Brønsted base. We also determined the reaction profiles for key oncogenic Ras mutants G12D and G12C using QM/MM minimizations, matching the experimentally observed loss of catalytic activity, thereby validating our reaction mechanism. Using the optimized reaction paths, we devised a fast and accurate procedure to design GAP mutants that activate G12D Ras. We replaced GAP residues near the active site and determined the activation barrier for 190 single mutants. We furthermore built a machine learning for ultrafast screening, by fast prediction of the barrier heights, tested both on the single and double mutations. This work demonstrates that fast and accurate screening can be accomplished via QM/MM reaction path optimizations to design protein sequences with increased catalytic activity. Several GAP mutations are predicted to re-enable catalysis in oncogenic G12D, offering a promising avenue to overcome aberrant Ras-driven signal transduction by activating enzymatic activity instead of inhibition. The outlined computational screening protocol is readily applicable for designing ligands and cofactors analogously.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.