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RESEARCH PRODUCT

Peptide Bond Formation Mechanism Catalyzed by Ribosome

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In this paper we present a study of the peptide bond formation reaction catalyzed by ribosome. Different mechanistic proposals have been explored by means of Free Energy Perturbation methods within hybrid QM/MM potentials, where the chemical system has been described by the M06-2X functional and the environment by means of the AMBER force field. According to our results, the most favorable mechanism in the ribosome would proceed through an eight-membered ring transition state, involving a proton shuttle mechanism through the hydroxyl group of the sugar and a water molecule. This transition state is similar to that described for the reaction in solution (J. Am. Chem. Soc. 2013, 135, 8708–8719), but the reaction mechanisms are noticeably different. Our simulations reproduce the experimentally determined catalytic effect of ribosome that can be explained by the different behavior of the two environments. While the solvent reorganizes during the chemical process involving an entropic penalty, the ribosome is preorganized in the formation of the Michaelis complex and does not suffer important changes along the reaction, dampening the charge redistribution of the chemical system. This work was supported by the Spanish Ministerio de Economía y Competitividad for project CTQ2012-36253-C03, Universitat Jaume I (project P1•1B2014-26), Generalitat Valenciana (PROMETEOII/2014/022), the Polish Ministry of Science and Higher Education (“Iuventus Plus” program project no. 0478/IP3/2015/73, 2015-2016) and the USA National Institute of Health (ref NIH R01 GM065368). Authors acknowledge computational resources from the Servei d’Informàtica of Universitat de València on the “Tirant” supercomputer and the Servei d’Informat́ica of Universitat Jaume I.