SARS-COV-2 M^pro conformational changes induced by covalently bound ligands

Abstract

SARS-CoV-2’s main protease (M^pro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, M^pro is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different M^pro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 μs per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the M^pro dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring in silico the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 M^pro.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• main protease
• M^pro
• Molecular dynamics simulation

Acknowledgements

The authors thank the CSC-IT Center for Science, Finland, for the generous computational resources. Authors also would like to thank Prof. Dr. Ewen MacDonald and Prof. Dr. Vinícius G. Maltarollo for the critical reading and language corrections.

Author contributions

G.M.F and T.K. designed the experiments, executed and analyzed the simulations. A.K.T. performed the WaterMap analysis. R.D.C.H., M.H.H and A.P. helped with the discussion and writing. M.H.H and A.P. contributed to resources and overall study supervision. All authors prepared and reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was partially supported by CNPq (Grant # 447120/2014-0) and FAPESP (Grant # 2016/12899-6 and 2019/24112-9), Brazil. MHH and RDCH are recipients of fellowships from CNPq, Brazil. GMF is a recipient of a fellowship from FAPESP, Brazil.