MD simulations indicate Omicron P132H of SARS-CoV-2 Mpro is a potential allosteric mutant involved in modulating the dynamics of catalytic site entry loop.

ABSTRACT

The SARS-CoV-2 main protease Mpro, essential for viral replication is an important drug target. It plays a critical role in processing viral polyproteins necessary for viral replication assembly. One of the predominant SARS-CoV-2 Mpro mutations of Omicron variant is Pro132His. Structurally, this mutation site is located ∼22 Å away from the catalytic site. The solved crystal structure of this mutant in complex with inhibitors as well as its reported catalytic efficiency did not show any difference with respect to the wild type. Thus, the mutation was concluded to be non-allosteric. Based on microsecond long MD simulation of the Pro132His mutant and wild type, we show that Pro132His mutation affects the conformational equilibrium with more population of conformational substates having open catalytic site, modulated by the dynamics of the catalytic site entry loop, implying the allosteric nature of this mutation. The structural analysis indicates that rearrangement of hydrogen bonds between His132 and adjacent residues enhances the dynamics of the linker, which in turn is augmented by the inherent dynamic flexibility of the catalytic pocket entry site due to the presence of charged residues. The altered dynamics leading to loss of secondary structures corroborate well with the reported compromised thermal stability.