ArticleProceedings of the National Academy of Sciences of the United States of America2013
Quantitative exploration of the molecular origin of the activation of GTPase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Mechanistic Insights into GTP Hydrolysis by the RhoA Protein: Catalytic Impact of Glutamine Tautomerism.ACS catalysis · 2025Article
- Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.bioRxiv : the preprint server for biology · 2024Article
- Arginine Kinase Activates Arginine for Phosphorylation by Pyramidalization and Polarization.ACS catalysis · 2024Article
- Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.Journal of the American Chemical Society · 2023Article
- Common Patterns of Hydrolysis Initiation in P-loop Fold Nucleoside Triphosphatases.Biomolecules · 2022Article
- Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials.Molecules (Basel, Switzerland) · 2021Article
- Structure-based inhibitor design of mutant RAS proteins-a paradigm shift.Cancer metastasis reviews · 2020Review
- A GAP-GTPase-GDP-PChemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- Water Distribution within Wild-Type NRas Protein and Q61 Mutants during Unrestrained QM/MM Dynamics.Biophysical journal · 2018Article
- Translation in Prokaryotes.Cold Spring Harbor perspectives in biology · 2018Review
- EF-Tu and EF-G are activated by allosteric effects.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Specific Substates of Ras To Interact with GAPs and Effectors: Revealed by Theoretical Simulations and FTIR Experiments.The journal of physical chemistry letters · 2018Article
- Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics.Journal of chemical theory and computation · 2017Article
- Metal Fluorides: Tools for Structural and Computational Analysis of Phosphoryl Transfer Enzymes.Topics in current chemistry (Cham) · 2017Review
- Ribosome dynamics during decoding.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2017Review
- Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin.Biochemistry · 2017Article
- The GTPase hGBP1 converts GTP to GMP in two stepsChemical science · 2017Article
- Exploring the mechanism of DNA polymerases by analyzing the effect of mutations of active site acidic groups in Polymerase β.Proteins · 2016Article
- Review: Translational GTPases.Biopolymers · 2016Review
- Invited review: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis.Biopolymers · 2016Review
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Authors and funding
4 authors.
Funding
Abstract
GTPases play a major role in cellular processes, and gaining quantitative understanding of their activation demands reliable free energy surfaces of the relevant mechanistic paths in solution, as well as the interpolation of this information to GTPases. Recently, we generated ab initio quantum mechanical/molecular mechanical free energy surfaces for the hydrolysis of phosphate monoesters in solution, establishing quantitatively that the barrier for the reactions with a proton transfer (PT) step from a single attacking water (1 W) is higher than the one where the PT is assisted by a second water (2 W). The implication of this finding on the activation of GTPases is quantified here, by using the ab initio solution surfaces to calibrate empirical valence bond surfaces and then exploring the origin of the activation effect. It is found that, although the 2 W PT path is a new element, this step is not rate determining, and the catalytic effect is actually due to the electrostatic stabilization of the pre-PT transition state and the subsequent plateau. Thus, the electrostatic catalytic effect found in our previous studies of the Ras GTPase activating protein (RasGAP) and the elongation factor-Tu (EF-Tu) with a 1 W mechanism is still valid for the 2 W path. Furthermore, as found before, the corresponding activation appears to involve a major allosteric effect. Overall, we believe that our finding is general to both GTPases and ATPases. In addition to the biologically relevant finding, we also provide a critical discussion of the requirements from reliable surfaces for enzymatic reactions.
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