A Pathway Model to Understand the Evolution of Spike Protein Binding to ACE2 in SARS-CoV-2 Variants

Abstract

After the SARS-CoV-2 Wuhan variant that gave rise to the pandemic, other variants named Delta, Omicron, and Omicron-2 sequentially became prevalent, with mutations spread around the viral genome, including on the spike (S) protein; in order to understand the resultant in gains in infectivity, we interrogated in silico both the equilibrium binding and the binding pathway of the virus' receptor-binding domain (RBD) to the angiotensin-converting enzyme 2 (ACE2) receptor. We interrogated the molecular recognition between the RBD of different variants and ACE2 through supervised molecular dynamics (SuMD) and classic molecular dynamics (MD) simulations to address the effect of mutations on the possible S protein binding pathways. Our results indicate that compensation between binding pathway efficiency and stability of the complex exists for the Omicron BA.1 receptor binding domain, while Omicron BA.2's mutations putatively improved the dynamic recognition of the ACE2 receptor, suggesting an evolutionary advantage over the previous strains.

Keywords: Sars-Cov-2; binding pathway; molecular dynamics; spike protein ACE-2; supervised molecular dynamics.

Figure 1

Comparison between SARS-CoV-2 RBD wild type and SARS-CoV-2 RBD Omicron: (A) SARS-2 WT RBD model showing residues T333-P527, with the original WT amino acids represented as liquorice. (B) SARS-2 WT RBD model showing residues T333-P527, with the Omicron mutations highlighted and represented as liquorice. With a total of 50 mutations, 15 of which are on the RBD, the Omicron variant possesses a different configuration of polar residues in the region between N477-H505 and a notable K417N mutation.

Figure 2

MD of ACE2 in complex with RBD^WT, RBD^Δ, and RBD°. (a) RMSD of RBD^WT, RBD^Δ, and RBD° over the time course of three 500 ns-long replicas (left panel, the curves were smoothed to interpolate the RMSD values) and the relative frequency distribution. (b) Comparison between the intermolecular contacts formed in ACE2:RBD^WT and ACE2:RBD^Δ complexes; red residues interacted more in ACE2:RBD^Δ, while blue residues were more engaged in ACE2:RBD^WT. (c) Comparison between the intermolecular contacts formed in ACE2:RBD^WT and ACE2:RBD° complexes; red residues interacted more in ACE2:RBD°, while blue residues were more engaged in ACE2:RBD^Δ. (d) Comparison between the per residue interaction energy in ACE2:RBD^WT and ACE2:RBD^Δ complexes; red residues stabilised ACE2:RBD^Δ, while blue residues stabilised more ACE2:RBD^Δ. (e) Comparison between the per residue interaction energy in ACE2:RBD^WT and ACE2:RBD° complexes; red residues stabilised ACE2:RBD^Δ, while blue residues stabilised more ACE2:RBD°.

Figure 3

SuMD binding of RBD^Δ, RBD°, and RBD^BA.2 to ACE2: (a–d) Snapshots of ACE2:RBD^WT, ACE2:RBD^Δ, RBD°, and RBD^BA.2 unstable complexes (MM-GBSA energy > 5 kcal mol⁻¹) from SuMD replicas. RBD^WT, RBD^Δ, RBD°, and RBD^BA.2 are coloured from blue to red to distinguish different frames; ACE2 in complex with RBD^WT is represented by a yellow ribbon. (e–h) Per residue energy decomposition of RBD^WT, RBD^Δ, RBD°, and RBD^BA.2 in the unstable states from SuMD binding simulations to ACE2; only frames with binding energy > 5 kcal mol⁻¹ were analysed.