Unveiling Mutation Effects on the Structural Dynamics of the Main
Protease from SARS-CoV-2 with Hybrid Simulation Methods
Abstract
The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for
processing polyproteins encoded by viral RNA. Macromolecules adopt
several favored conformations in solution depending on their structure
and shape, determining their dynamics and function. Integrated methods
combining the lowest-frequency movements obtained by Normal Mode
Analysis (NMA), and the faster movements from Molecular Dynamics (MD),
and data from biophysical techniques, are necessary to establish the
correlation between complex structural dynamics of macromolecules and
their function. In this article, we used a hybrid simulation method to
sample the conformational space to characterize the structural dynamics
and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including
several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and
B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD
have been useful to study the correlation between the complex structural
dynamics of macromolecules and their functioning mechanisms. Here, we
applied this hybrid approach to elucidate the effects of mutation in the
structural dynamics of SARS-CoV-2 Mpro, considering their flexibility,
solvent accessible surface area analyses, global movements, and
catalytic dyad distance. Furthermore, some mutants showed significant
changes in their structural dynamics and conformation, which could lead
to distinct functional properties.