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Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart?A crystallographic,biophysical,and theoretical study

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hLife 2024年第8期2卷 419-433页

作者： Mohamed Ibrahim xinyuanyuan sun Vinicius Martins de Oliveira Ruibin Liu Joseph Clayton Haifa El Kilani Jana Shen Rolf Hilgenfeld Institute of Molecular Medicine University of Lübeck23562 LübeckGermany Department of Pharmaceutical Sciences University of Maryland School of PharmacyBaltimoreMD 21201USA Division of Applied Regulatory Science Office of Clinical PharmacologyOffice of Translational SciencesCenter for Drug Evaluation and ResearchUnited States Food and Drug AdministrationSilver SpringMD 20993USA German Center for Infection Research(DZIF) Hamburg-Lübeck-Borstel-Riems SiteUniversity of Lübeck23562 LübeckGermany

During the continuing evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November of that *** with its sublineages,it has maintained a prominent role ever *** Nsp5 main protease(Mpro)of the Omicron virus is characterized by a single dominant mutation,*** we determined the X-ray crystal structures of the P132H mutant(or O-Mpro)as a free enzyme and in complex with the Mpro inhibitor,the alpha-ketoamide 13b-K,and we conducted enzymological,biophysical,as well as theoretical studies to characterize the *** found that O-Mpro has a similar overall structure and binding with 13b-K;however,it displays lower enzymatic activity and lower thermal stability compared to the WT-Mpro(with“WT”referring to the prototype strain).Intriguingly,the imidazole ring of His132 and the carboxylate plane of Glu240 are in a stacked configuration in the X-ray structures determined *** folding free energy calculations suggest that the O-Mpro dimer is destabilized relative to the WT-Mpro due to less favorable van der Waals interactions and backbone conformations in the individual ***-atom continuous constant-pH molecular dynamics(MD)simulations reveal that His132 and Glu240 display coupled *** pH 7,His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is *** order to examine whether the Omicron mutation eases the emergence of further Mpro mutations,we also analyzed the P132H+T169S double mutant,which is characteristic of the BA.1.1.2 ***,we found little evidence of a correlation between the two mutation sites.

关键词： severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) main protease Omicron molecular dynamics Pro>His mutant double mutant

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