Bibliographic Details
| Title: |
Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study |
| Authors: |
Mohamed Ibrahim, Xinyuanyuan Sun, Vinicius Martins de Oliveira, Ruibin Liu, Joseph Clayton, Haifa El Kilani, Jana Shen, Rolf Hilgenfeld |
| Source: |
hLife, Vol 2, Iss 8, Pp 419-433 (2024) |
| Publisher Information: |
Elsevier, 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Medicine |
| Subject Terms: |
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), main protease, Omicron, molecular dynamics, Pro>His mutant, double mutant, Medicine |
| More Details: |
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 year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main protease (Mpro) of the Omicron virus is characterized by a single dominant mutation, P132H. Here 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 O-Mpro. We 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 here. Empirical 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 protomers. All-atom continuous constant-pH molecular dynamics (MD) simulations reveal that His132 and Glu240 display coupled titration. At pH 7, His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is charged. In 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 lineage. However, we found little evidence of a correlation between the two mutation sites. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2949-9283 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S294992832400049X; https://doaj.org/toc/2949-9283 |
| DOI: |
10.1016/j.hlife.2024.06.003 |
| Access URL: |
https://doaj.org/article/267a1214c0c245738d97eb6061005e8c |
| Accession Number: |
edsdoj.267a1214c0c245738d97eb6061005e8c |
| Database: |
Directory of Open Access Journals |
