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

07 July 2020, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

3CL protease
SARS-CoV-2
Minimum Free Energy Path
QM/MM
Acylation
De-acylation
Molecular Dynamics

Supplementary materials

Title
Description
Actions
Title
SI 3CL v2
Description
Actions
Title
Acylation
Description
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Title
Deacylation
Description
Actions

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