Improved Binding Affinity of Omicron's Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence

Abstract

The new variant of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including the spike protein's receptor-binding domain (RBD). We have computationally investigated the interaction between the RBD of both the wild type and Omicron variant of SARS-CoV-2 with the human angiotensin-converting enzyme 2 (hACE2) receptor using molecular dynamics and molecular mechanics-generalized Born surface area (MM-GBSA)-based binding free energy calculations. The mode of the interaction between Omicron's RBD with the hACE2 receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The binding free energy difference shows that the spike protein of Omicron has an increased affinity for the hACE2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g., S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. A pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to the binding free energies and suggests that this is one of the key interactions stabilizing the formation of the complex. The resulting structural insights into the RBD:hACE2 complex, the binding mode information within it, and residue-wise contributions to the free energy provide insight into the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

Keywords: Omicron; human angiotensin-converting enzyme 2 (hACE2); molecular dynamics simulation; molecular mechanics-generalized Born surface area (MM-GBSA); receptor-binding domain (RBD); receptor-binding motif (RBM); severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).

Figure 1

The coronavirus spike protein domain architecture and sequence alignment of the original RBD of SARS-CoV-2 and the RBD of the Omicron variant. Asterisks denote identical amino acid residues. The red rectangular box indicates the receptor-binding motif of RBD. NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; HR, heptad repeat.

Figure 2

Comparative sequences analysis of the spike RBM of SARS-CoV-2. A total of 34 representative sequences were aligned. Asterisks denote identical amino acid residues.

Figure 3

(a) Residue-wise contributions for the binding free energies. The results are shown only for residues in the RBD of the spike protein. Further, the numbering of residues is shifted by three for the Omicron to account for the three deletions. (b) The difference in residue-wise contributions to the binding free energies between the spike proteins of the Omicron variant and the wild type (wt).

Figure 4

The electrostatic interaction involving residues and their interactions observed during MD simulation: (a) All possible salt bridge pairs Arg493 -- Asp30, Arg493 -- Glu35, and Arg498 -- Asp38 observed during the entire 100 ns MD simulation, (b) the salt bridge pairs Arg493 -- Asp30 and Arg498 -- Asp38 observed between 0 and 70 ns of MD simulation, (c) the salt bridge pair Arg493 -- Glu35 observed between 80 and 100 ns of MD simulation, and (d) the salt bridge pairs Arg493 -- Glu35 and Arg498 -- Asp38 observed for a very short time between 80 and 85 ns of MD simulation. The hACE2 receptor is shown in blue and the spike RBD by orange.

Figure 5

Salt bridges interactions and their corresponding distances between the wild type spike RBD and the hACE2 receptor complex during 100 ns of MD simulation.

Figure 6

The distance between residues participating in the salt bridge (electrostatic interaction) during the entire MD simulation.