Assessment of mutations on RBD in the Spike protein of SARS-CoV-2 Alpha, Delta and Omicron variants

Abstract

The severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) variant Omicron spread more rapid than the other variants of SARS-CoV-2 virus. Mutations on the Spike (S) protein receptor-binding domain (RBD) are critical for the antibody resistance and infectivity of the SARS-CoV-2 variants. In this study, we have used accelerated molecular dynamics (aMD) simulations and free energy calculations to present a systematic analysis of the affinity and conformational dynamics along with the interactions that drive the binding between Spike protein RBD and human angiotensin-converting enzyme 2 (ACE2) receptor. We evaluate the impacts of the key mutation that occur in the RBDs Omicron and other variants in the binding with the human ACE2 receptor. The results show that S protein Omicron has stronger binding to the ACE2 than other variants. The evaluation of the decomposition energy per residue shows the mutations N440K, T478K, Q493R and Q498R observed in Spike protein of SARS-CoV-2 provided a stabilization effect for the interaction between the SARS-CoV-2 RBD and ACE2. Overall, the results demonstrate that faster spreading of SARS-CoV-2 Omicron may be correlated with binding affinity of S protein RBD to ACE2 and mutations of uncharged residues to positively charged residues such as Lys and Arg in key positions in the RBD.

Figure 1

RMSD for RBD_WT–ACE2, RBD_Alpha–ACE2, RBD_Omicron–ACE2 and RBD_Delta–ACE2 complexes.

Figure 2

Three-dimensional structure of ACE2 and RBD with RMSF regions for SARS-CoV-2, Alpha, Delta and Omicron systems.

Figure 3

Movements described for the first principal component (PC1) for each structure of ACE2 and RBD. (a) Moving in PC1 to the RBD_WT complex (SARS-CoV-2) and ACE2 receptor. (b) changes in PC1 to RBD_Alpha and ACE2. (c) Change moving of PC1 to RBD_Delta and ACE2. (d) Moving from PC1 to the complex between RBD_Omicron and ACE2. In turquoise, the initial structure of the movement, in dark magenta, the final structure and in gray, the intermediate structures of the movement. The conformational dynamics were obtained from 200 ns of aMD simulations.

Figure 4

(a) Three-dimensional structure of the RBD_WT and ACE2 complex with the electrostatic energy regions. (b) Decomposition energy per residue for the RBD_WT system connected to ACE2. The label in orange is from the ACE2 region and in purple is from RBD.