tetano
Editor, Senior Moderator
Structure
. 2022 May 26;S0969-2126(22)00180-0.
doi: 10.1016/j.str.2022.05.006. Online ahead of print.
Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein
Lorena Zuzic[SUP] 1 [/SUP], Firdaus Samsudin[SUP] 2 [/SUP], Aishwary T Shivgan[SUP] 2 [/SUP], Palur V Raghuvamsi[SUP] 3 [/SUP], Jan K Marzinek[SUP] 2 [/SUP], Alister Boags[SUP] 4 [/SUP], Conrado Pedebos[SUP] 5 [/SUP], Nikhil K Tulsian[SUP] 6 [/SUP], Jim Warwicker[SUP] 7 [/SUP], Paul MacAry[SUP] 8 [/SUP], Max Crispin[SUP] 9 [/SUP], Syma Khalid[SUP] 10 [/SUP], Ganesh S Anand[SUP] 11 [/SUP], Peter J Bond[SUP] 12 [/SUP]
Affiliations
Abstract
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.
Keywords: COVID-19; benzene mapping; coronavirus; cryptic pockets; glycans; hydrogen-deuterium exchange mass spectrometry; molecular dynamics simulation; omicron; spike protein.
. 2022 May 26;S0969-2126(22)00180-0.
doi: 10.1016/j.str.2022.05.006. Online ahead of print.
Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein
Lorena Zuzic[SUP] 1 [/SUP], Firdaus Samsudin[SUP] 2 [/SUP], Aishwary T Shivgan[SUP] 2 [/SUP], Palur V Raghuvamsi[SUP] 3 [/SUP], Jan K Marzinek[SUP] 2 [/SUP], Alister Boags[SUP] 4 [/SUP], Conrado Pedebos[SUP] 5 [/SUP], Nikhil K Tulsian[SUP] 6 [/SUP], Jim Warwicker[SUP] 7 [/SUP], Paul MacAry[SUP] 8 [/SUP], Max Crispin[SUP] 9 [/SUP], Syma Khalid[SUP] 10 [/SUP], Ganesh S Anand[SUP] 11 [/SUP], Peter J Bond[SUP] 12 [/SUP]
Affiliations
- PMID: 35660160
- DOI: 10.1016/j.str.2022.05.006
Abstract
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.
Keywords: COVID-19; benzene mapping; coronavirus; cryptic pockets; glycans; hydrogen-deuterium exchange mass spectrometry; molecular dynamics simulation; omicron; spike protein.