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Institut de Química Computacional i Catàlisi

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 ?s) 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 ?5 and sheet ?5, 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.

This work has been performed in collaboration of Dr. A. S. F. Oliveira and Prof. A. J. Mulholland (University of Bristol), Prof. S. A. Serapian and Prof. Giorgio Colombo (University of Pavia, Italy), and Prof. Sílvia Osuna of the TCBioSys group of the Institute of Computational Chemistry and Catalysis (IQCC) of the University of Girona.

It has been recently published open access in Journal of the American Chemical Society:

M. Castelli, F. Marchetti, S. Osuna, A. S. F. Oliveira, A. J. Mulholland, S. A. Serapian*, and G. Colombo*

“Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics Simulations

J. Am. Chem. Soc., 2024, 146, 901-919

DOI: 10.1021/jacs.3c11396


Girona, January 15, 2024
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