The SARS-CoV-2 main protease (Mpro) protein plays an important role in the viral life cycle, and due to the lack of homologous structures in humans, is a good target for small molecule inhibitors. During the 2020 coronavirus pandemic, the Voelz Lab participated in a project to crowdsource the discovery of new SARS-CoV-2 main protease (Mpro) inhibitors as part of the COVID Moonshot initiative, through the use of massively parallel absolute bindng free energy calculations performed on the Folding@home distributed computing platform. These calculations used the monomeric form of the Mpro receptor, while it is known experimentally that Mpro is only active as a dimer.   To examine the integrity of the Mpro active site during these calculations, we perform a retrospective study of the simulation trajectory data generated during the Moonshot calculations.  Through the measurement of atom distances and dihedral angles in the Mpro active site, we identify several key features that, when compared to experimental crystallographic structures of Mpro bound to small molecule inhibitors, quantify the extent to which the active site falls apart or maintains its structural integrity.  Time-lagged independent component analysis (tICA) was performed to identify the slowest motions in the simulations, and compute the rates and pathways of inactivation.  These results challenge some assumptions common in computational drug discovery, with particular implications for Mpro.

Structural and dynamical analysis of monomeric SARS-CoV-2 Mpro active site integrity

ACS Spring 2022

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