Comparative Computational Analysis of Spike Protein Structural Stability in SARS-CoV-2 Omicron Subvariants

Abstract

The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike (S) protein mutations pose serious threats to current coronavirus disease 2019 (COVID-19) therapies. A comprehensive understanding of the structural stability of SARS-CoV-2 variants is vital for the development of effective therapeutic strategies as it can offer valuable insights into their potential impact on viral infectivity. S protein mediates a virus' attachment to host cells by binding to angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD), and mutations in this protein can affect its stability and binding affinity. We analyzed S protein structural stability in various Omicron subvariants computationally. Notably, the S protein sequences analyzed in this work were obtained directly from our own sample collection. We evaluated the binding free energy between S protein and ACE2 in several complex forms. Additionally, we measured distances between the RBD of each chain in S protein to analyze conformational changes. Unlike most of the prior studies, we analyzed full-length S protein-ACE2 complexes instead of only RBD-ACE2 complexes. Omicron subvariants including BA.1, BA.2, BA.2.12.1, BA.4/BA.5, BA.2.75, BA.2.75_K147E, BA.4.6 and BA.4.6_N658S showed enhanced stability compared to wild type, potentially due to distinct S protein mutations. Among them, BA.2.75 and BA.4.6_N658S exhibited the highest and lowest level of stability, respectively.

Keywords: MD simulation; MM/PBSA; Omicron; SARS-CoV-2.

Figure 1

RMSD plot of the protein backbone atoms in the one-open-complex form during 10 ns MD simulation. (a) Wild type, (b) BA.1, (c) BA.2, (d) BA.2.12.1, (e) BA.4/BA.5, (f) BA.2.75, (g) BA.2.75_K147E, (h) BA.4.6 and (i) BA.4.6_N658S. X axis denotes the MD simulation time (ps) and Y axis denotes the RMSD value (nm).

Figure 2

The RMSD plot of the protein backbone atoms in the two-open-complex form during 10 ns MD simulation. (a) Wild type, (b) BA.1, (c) BA.2, (d) BA.2.12.1, (e) BA.4/BA.5, (f) BA.2.75, (g) BA.2.75_K147E, (h) BA.4.6 and (i) BA.4.6_N658S. X axis denotes the MD simulation time (ps) and Y axis denotes the RMSD value (nm).

Figure 3

The RMSD plot of the protein backbone atoms in the three-open-complex form during 10 ns MD simulation. (a) Wild type, (b) BA.1, (c) BA.2, (d) BA.2.12.1, (e) BA.4/BA.5, (f) BA.2.75, (g) BA.2.75_K147E, (h) BA.4.6 and (i) BA.4.6_N658S. X axis denotes the MD simulation time (ps) and Y axis denotes the RMSD value (nm).

Figure 4

Structures of full-length SARS-CoV-2 S protein–ACE2 complex. The trimeric chains of the S protein are depicted in purple, brown and magenta colors, denoted as A, B and C, respectively. The ACE2 receptors, denoted as I, II and III, are depicted in the red color.

Figure 5

A representation of SARS-CoV-2 binding interface residues N501 and V503 forming the threefold symmetry with the same distance among trimeric RBD chains in the closed (PDB 6VXX) and 3-open-complex (PDB 7A98) forms. Trimeric chains (A, B and C) of S protein are shown in purple, brown and magenta colors, respectively.

Figure 6

The standard deviations for distances between V503 residues in each chain for the final MD trajectory (10 ns). (a) One-open-complex form, (b) two-open-complex form and (c) three-open-complex form. X axis denotes the variant type and Y axis denotes the standard deviation for distance (nm). Blue indicates the standard deviation (SD) between the AB and BC chains, orange indicates the SD between the AB and AC chains, gray indicates the SD between the AC and BC chains and yellow indicates the SD among the A, B, and C chains.

Figure 7

The standard deviations for distances between N501 residues in each chain of the S protein for the final MD trajectory (10 ns). (a) One-open-complex form, (b) two-open-complex form and (c) three-open-complex form. X axis denotes the variant type and Y axis denotes the standard deviation for distance (nm). Blue indicates the standard deviation (SD) between the AB and BC chains, orange indicates the SD between the AB and AC chains, gray indicates the SD between the AC and BC chains and yellow indicates the SD among the A, B, and C chains.