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Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods

revised on 07.07.2020, 07:52 and posted on 07.07.2020, 09:50 by Carlos A. Ramos-Guzmán, J. Javier Ruiz-Pernía, Iñaki Tuñón

We present a detailed theoretical analysis of the reaction mechanism of proteolysis catalyzed by the main protease of SARS-CoV-2. Using multiscale simulation methods, we have characterized the interactions stablished by a peptidic substrate in the active site and then we have explored the free energy landscape associated to the acylation and de-acylation steps of the proteolysis reaction, characterizing the transition states of the process. Our mechanistic proposals can explain most of the experimental observations made on the highly similar ortholog protease of SARS-CoV. We point out to some key interactions that may facilitate the acylation process and thus can be crucial in the design of more specific and efficient inhibitors of the main protease activity. In particular, from our results, the P1’ residue can be a key factor to improve the thermodynamics and kinetics of the inhibition process.


Ministerio de Ciencia, Innovación y Universidades PGC2018-094852-B-C22



Email Address of Submitting Author


Universidad de Valencia



ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest


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