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Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein

2022; Elsevier BV; Volume: 30; Issue: 8 Linguagem: Inglês

10.1016/j.str.2022.05.006

1878-4186

Lorena Zuzic, Firdaus Samsudin, Aishwary T. Shivgan, Palur Venkata Raghuvamsi, Jan K. Marzinek, Alister Boags, Conrado Pedebos, Nikhil Kumar Tulsian, Jim Warwicker, Paul A. MacAry, Max Crispin, Syma Khalid, Ganesh S. Anand, Peter J. Bond,

RNA and protein synthesis mechanisms

The COVID-19 pandemic has prompted a rapid response in vaccine and drug development. Herein, we modeled a complete membrane-embedded SARS-CoV-2 spike glycoprotein and used molecular dynamics simulations with benzene probes designed to enhance discovery of cryptic pockets. This approach recapitulated lipid and host metabolite binding sites previously characterized by cryo-electron microscopy, revealing likely ligand entry routes, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop. A full representation of glycan moieties was essential to accurately describe pocket dynamics. A multi-conformational behavior of the 617-628 loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility found in SARS-CoV-2 variants of concern including Omicron. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.