Structural dynamics of the β-coronavirus Mpro protease ligand binding sites

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

β-coronaviruses alone have 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 back-up against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensible role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV and MERS-CoV Mpro. Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across β-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-coronavirus homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.