loading page

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods
  • +6
  • Eric Philot,
  • Angelo Magro,
  • Patrícia Ggasparini,
  • Jean Carlos de Mattos,
  • Natanael Endrew Torres-Bonfim,
  • Roberto Quiroz,
  • André Klioussof ,
  • David Perahia,
  • ANA LÍGIA SCOTT
Eric Philot
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
Angelo Magro
UNESP
Author Profile
Patrícia Ggasparini
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
Jean Carlos de Mattos
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
Natanael Endrew Torres-Bonfim
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
Roberto Quiroz
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
André Klioussof
Federal University of ABC Center of Mathematics Computing and Cognition
Author Profile
David Perahia
Ecole Normale Supérieure de Cachan
Author Profile
ANA LÍGIA SCOTT
Federal University of the ABC
Author Profile

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.

Peer review status:UNDER REVIEW

27 Jul 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
30 Jul 2021Assigned to Editor
30 Jul 2021Submission Checks Completed
27 Aug 2021Reviewer(s) Assigned
24 Sep 2021Review(s) Completed, Editorial Evaluation Pending