In Silico Substrate-Binding Profiling for SARS-CoV-2 Main Protease (Mpro) Using Hexapeptide Substrates

Author:

Zabo Sophakama1ORCID,Lobb Kevin Alan1ORCID

Affiliation:

1. Department of Chemistry, Rhodes University, Makhanda 6139, South Africa

Abstract

The SARS-CoV-2 main protease (Mpro) is essential for the life cycle of the COVID-19 virus. It cleaves the two polyproteins at 11 positions to generate mature proteins for virion formation. The cleavage site on these polyproteins is known to be Leu-Gln↓(Ser/Ala/Gly). A range of hexapeptides that follow the known sequence for recognition and cleavage was constructed using RDKit libraries and complexed with the crystal structure of Mpro (PDB ID 6XHM) through extensive molecular docking calculations. A subset of 131 of these complexes underwent 20 ns molecular dynamics simulations. The analyses of the trajectories from molecular dynamics included principal component analysis (PCA), and a method to compare PCA plots from separate trajectories was developed in terms of encoding PCA progression during the simulations. The hexapeptides formed stable complexes as expected, with reproducible molecular docking of the substrates given the extensiveness of the procedure. Only Lys-Leu-Gln*** (KLQ***) sequence complexes were studied for molecular dynamics. In this subset of complexes, the PCA analysis identified four classifications of protein motions across these sequences. KLQ*** complexes illustrated the effect of changes in substrate on the active site, with implications for understanding the substrate recognition of Mpro and informing the development of small molecule inhibitors.

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

Reference39 articles.

1. WHO (2023, May 06). Coronavirus Disease (COVID-19) Pandemic. World Health Organization. Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

2. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases;Liu;ACS Cent. Sci.,2020

3. New insights of emerging SARS-CoV-2: Epidemiology, etiology, clinical features, clinical treatment, and prevention;Guo;Front. Cell Dev. Biol.,2020

4. Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S.C., and Di Napoli, R. (2020, July 18). Features, Evaluation, and Treatment of Coronavirus (COVID-19), StatPearls, Available online: https://www.ncbi.nlm.nih.gov/books/NBK554776/.

5. Tu, Y.F., Chien, C.S., Yarmishyn, A.A., Lin, Y.Y., Luo, Y.H., Lin, Y.T., Lai, W.Y., Yang, D.M., Chou, S.J., and Yang, Y.P. (2020). A review of SARS-CoV-2 and the ongoing clinical trials. Int. J. Mol. Sci., 21.

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