Omicron Binding Mode: Contact Analysis and Dynamics of the Omicron Receptor-Binding Domain in Complex with ACE2

On 26 November 2021, the WHO classified the Omicron variant
of
the SARS-CoV-2 virus (B.1.1.529 lineage) as a variant of concern (VOC)
(COVID-19 Variant Data, Department of Health, 2022). The Omicron variant contains as many as 26 unique mutations
of effects not yet determined (Venkatakrishnan, A., Open Science
Framework, 2021). Out of its total of 34 Spike protein mutations,
15 are located on the receptor-binding domain (S-RBD) (Stanford
Coronavirus Antiviral & Resistance Database, 2022) that
directly contacts the angiotensin-converting enzyme 2 (ACE2) host
receptor and is also a primary target for antibodies. Here, we studied
the binding mode of the S-RBD domain of the Spike protein carrying
the Omicron mutations and the globular domain of human ACE2 using
molecular dynamics (MD) simulations. We identified new and key Omicron-specific
interactions such as R493 (of mutation Q493R), which forms
salt bridges both with E35 and D38 of ACE2,
Y501 (N501Y), which forms an edge-to-face aromatic interaction
with Y41, and Y505 (Y505H), which makes an H-bond
with E37 and K353. The glycan chains of ACE2
also bind differently in the WT and Omicron variants in response to
different charge distributions on the surface of Spike proteins. However,
while the Omicron mutations considerably improve the overall electrostatic
fit of the two interfaces, the total number of specific and favorable
interactions between the two does not increase. The dynamics of the
complexes are highly affected too, making the Omicron S-RBD:ACE2 complex
more rigid; the two main interaction sites, Patches I and II, isolated
in the WT complex, become connected in the Omicron complex through
the alternating interaction of R493 and R498 with E35 and D38.