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

Cho, E.; Rosa, M.; Anjum, R.; Mehmood, S.; Soban, M.; Mujtaba, M.; Bux, K.; Dantu, S. C.; Pandini, A.; Yin, J.; Ma, H.; Ramanathan, A.; Islam, B.; Mey, A.; BHOWMIK, D.; Haider, S.

doi:10.1101/2021.03.31.437918

bioRxiv · 10.1101/2021.03.31.437918

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

Cho, E.·Rosa, M.·Anjum, R.·Mehmood, S.·Soban, M.·Mujtaba, M.·Bux, K.·Dantu, S. C.·Pandini, A.·Yin, J.·Ma, H.·Ramanathan, A.·Islam, B.·Mey, A.·BHOWMIK, D.·Haider, S.

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Abstract

{beta}-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 {beta}-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across {beta}-coronavirus homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.

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Cho, E., Rosa, M., Anjum, R., Mehmood, S., Soban, M., Mujtaba, M., Bux, K., Dantu, S. C., Pandini, A., Yin, J., Ma, H., Ramanathan, A., Islam, B., Mey, A., BHOWMIK, D., Haider, S.. 2021-04-01. Structural dynamics of the β-coronavirus Mpro protease ligand binding sites. https://doi.org/10.1101/2021.03.31.437918

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