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Abstract
Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different “languages”: allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (e.g., mutations). To accurately model allostery, unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, e.g., detect incipient allosteric changes or likely perturbation pathways; this is because allostery can operate at longer time scales than those accessible by plain MD. Such methods are typically applied singularly, but we here argue their joint application─as a “multilingual” approach─could work significantly better. We successfully prove this through unbiased MD simulations (∼100 μs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, from which we decrypt allostery using four showcase “languages”: Distance Fluctuation analysis and the Shortest Path Map capture allosteric hotspots at equilibrium; Anisotropic Thermal Diffusion and Dynamical Non-Equilibrium MD simulations assess perturbations upon, respectively, either superheating or hydrolyzing the GTP that oncogenically activates K-Ras4B. Chosen “languages” work synergistically, providing an articulate, mutually coherent, experimentally consistent picture of K-Ras4B allostery, whereby distinct traits emerge at equilibrium and upon GTP cleavage. At equilibrium, combined evidence confirms prominent allosteric communication from the membrane-embedded hypervariable region, through a hub comprising helix α5 and sheet β5, and up to the active site, encompassing allosteric “switches” I and II (marginally), and two proposed pockets. Upon GTP cleavage, allosteric perturbations mostly accumulate on the switches and documented interfaces.
Original language | English |
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Pages (from-to) | 901-919 |
Number of pages | 19 |
Journal | Journal of the American Chemical Society |
Volume | 146 |
Issue number | 1 |
Early online date | 20 Dec 2023 |
DOIs | |
Publication status | Published - 10 Jan 2024 |
Bibliographical note
Publisher Copyright:© 2023 The Authors. Published by American Chemical Society.
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Dive into the research topics of 'Decrypting allostery in membrane-bound K-Ras4B using complementary in silico approaches based on unbiased molecular dynamics simulations'. Together they form a unique fingerprint.Projects
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PREDACTED: Predictive simulation for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Design
Mulholland, A. J. (Principal Investigator)
1/08/21 → 31/07/26
Project: Research, Parent
Equipment
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HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities
Alam, S. R. (Manager), Williams, D. A. G. (Manager), Eccleston, P. E. (Manager) & Greene, D. (Manager)
Facility/equipment: Facility