Dynamic Profiling of β-Coronavirus 3CL M(pro) Protease Ligand-Binding Sites

Cho, Eunice; Rosa, Margarida; Anjum, Ruhi; Mehmood, Saman; Soban, Mariya; Mujtaba, Moniza; Bux, Khair; Moin, Syed T.; Tanweer, Mohammad; Dantu, Sarath; Pandini, Alessandro; Yin, Junqi; Ma, Heng; Ramanathan, Arvind; Islam, Barira; Mey, Antonia S. J. S.; Bhowmik, Debsindhu; Haider, Shozeb

[Image: see text] β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (M(pro)) that plays an indispensable role in viral replication. The availability of over 270 M(pro) X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV M(pro). Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three M(pro) enzymes with a single pan inhibitor.