The hypermutated receptor binding domain (RBD) of the Omicron (B.1.1.529) lineage exhibits a different binding interface with human angiotensin-converting enzyme 2 (ACE2) relative to that of the wild-type Wuhan Hu-1, yet how the altered interaction will affect viral evolution is largely unknown. Here, we used molecular dynamics simulation to characterize the binding features of the Omicron BA.1/hACE2 complex and used free energy perturbation calculations to assess the ongoing and putative variations. The complex reveals a substantial rearrangement of the interfacial hydrogen-bond network: R493 of RBD forms a dynamic electrostatic interaction with both E35 and D38 of hACE2, which prohibits the hydrogen bonds of R498-D38 and Y449-D38. Whereas most circulating mutations minimally affect RBD binding to hACE2, the charge-altering mutation R493Q attenuates the affinity by abolishing the electrostatic interaction. However, the potential variants H505Y or N417K/R493Q could restore and gain even greater binding affinities than BA.1 as a result of their optimized interaction network and epistasis effects.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Physical Chemistry Letters|
|State||Published - Sep 29 2022|
Bibliographical noteFunding Information:
The authors acknowledge the financial support from the Shenzhen Municipal Science and Technology Innovation Commission (KQTD2017-0330155106581) and the National Natural Science Foundation of China (22007069) for work performed at the Shenzhen Bay Laboratory Supercomputing Centre.
© 2022 American Chemical Society.
PubMed: MeSH publication types
- Journal Article