Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces

Abstract

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here, we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2 [hACE2]) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild-type strain. Our key findings are that glycans play a vital role at the RBD···hACE2 interface for the Omicrons, and the interplay between glycans and sequence mutations leads to enhanced binding. We find significant structural differences in the complexes, which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild-type. However, further differences between subvariants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: mutations reduce interdomain interactions between the up chain and its clockwise neighbor chain in particular for the latter, resulting in enhanced flexibility for BA.2. Consequently, we see occurrence of additional close contacts in one replica of BA.2, which include binding to hACE2 by a second RBD in addition to the up chain. Although this motif is not seen in BA.1, we find that the Omicrons can directly/indirectly bind a down-RBD to hACE2 through glycans: the role of the glycan on N90 of hACE2 switches from inhibiting to facilitating the binding to Omicron spike protein via glycan-protein lateral interactions. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

Figure 1

Representations of the quaternary structure of the spike protein and hACE2 highlighting the S trimer chains A–C, key domain structure—NTD (residues 16–291) and RBD (residues 330–530)—and bound glycans.

Figure 2

From RL: S+hACE2 complexes involving WT (cyan) and BA.2 (red), aligned with RBD-A, it is clear that RBD-C of BA.2 is drawn closer to hACE2 (with interaction at the location of the dashed circle).

Figure 3

BA.2 (RL): changes in charged contacts between hACE2 and RBD-A (see Table 2): K417_A (WT)···D30_hACE2 (top center) was abolished after mutation of K417N (top right, where D30_hACE2 are depicted in pale ball-and-stick); lower row, Q493_A···E35_hACE2···K31_hACE2 (bottom center, where D38_hACE2 and K353_hACE2 are in pale ball-and-stick) changed to Q493R_A···D38_hACE2···K353_hACE2 (bottom right, where E35_hACE2 and K31_hACE2 are in pale ball-and-stick).

Figure 4

BA.2 (RL): hydrophobic contacts F486_A···L85_hACE2, D405N/Y505H_A···A386/A387_hACE2, and charged contact N440K_A···E329_hACE2.

Figure 5

BA.2 (RL): interfacial charged contact E564_hACE2···Q498R_C.

Figure 6

RMSF profiles for RBD-C of S-protein: RL (a) and RS (b): RBD-C of the Omicrons has higher RMSF than that of WT.

Figure 7

(a) Relative positions of RBD-A and RBD-C of BA.1 (cyan) and BA.2 (red). Aligned with RBD-A, it can be seen that RBD-C of BA.2 is further away from its RBD-A than BA.1. In the foreground are D428_A···R408_C (blue) for BA.1, and residues R408S_C of BA.2 (orange). In the background are E484A_C of BA.1 (blue) and BA.2 (orange). (b) Viewing from the inner cavity side, RBD-A and RBD-C are so decoupled that $\overline{\mathrm{N}}$90_hACE2 (blue spheres) can even occupy the gap in between. (Corresponding figures for RS are shown in Fig. S13).

Figure 8

Positions of glycans $\overline{\mathrm{N}}$90_hACE2 (blue) and $\overline{\mathrm{N}}$165_NTD-A (pink) relative to hACE2 (lilac) and RBDs—RBD-A (cyan), RBD-B (yellow), RBD-C (lime)—at the end of 1 μs. The interface is widest for the WT, and narrowest for BA.2.