Dynamics of water-mediated interaction effects on the stability and transmission of Omicron

Abstract

SARS-Cov-2 Omicron variant and its highly transmissible sublineages amidst news of emerging hybrid variants strengthen the evidence of its ability to rapidly spread and evolve giving rise to unprecedented future waves. Owing to the presence of isolated RBD, monomeric and trimeric Cryo-EM structures of spike protein in complex with ACE2 receptor, comparative analysis of Alpha, Beta, Gamma, Delta, and Omicron assist in a rational assessment of their probability to evolve as new or hybrid variants in future. This study proposes the role of hydration forces in mediating Omicron function and dynamics based on a stronger interplay between protein and solvent with each Covid wave. Mutations of multiple hydrophobic residues into hydrophilic residues underwent concerted interactions with water leading to variations in charge distribution in Delta and Omicron during molecular dynamics simulations. Moreover, comparative analysis of interacting moieties characterized a large number of mutations lying at RBD into constrained, homologous and low-affinity groups referred to as mutational drivers inferring that the probability of future mutations relies on their function. Furthermore, the computational findings reveal a significant difference in angular distances among variants of concern due 3 amino acid insertion (EPE) in Omicron variant that not only facilitates tight domain organization but also seems requisite for characterization of mutational processes. The outcome of this work signifies the possible relation between hydration forces, their impact on conformation and binding affinities, and viral fitness that will significantly aid in understanding dynamics of drug targets for Covid-19 countermeasures. The emerging scenario is that hydration forces and hydrophobic interactions are crucial variables to probe in mutational analysis to explore conformational landscape of macromolecules and reveal the molecular origins of protein behaviors.

Figure 1

Normal mode analysis (NMA) of Dynamut demonstrating comparative thermodynamic effect of mutations on stability and flexibility of spike protein of all VoCs. Differences in free energy (ΔΔG) and variations in vibrational entropy (ΔΔS_Vib ENCoM) between the WT and other VoCs are mentioned from lowest to highest.

Figure 2

(a) Intermolecular interactions of recently emerged mutations in Omicron RBD with neighboring residues and solvent during 300 ns MD simulations (b) Homologous and presumably constrained interacting residues among all VoCs exhibit significant interactions with induced mutations. (+/−) signifies the charge. (c) Recently evolved mutations from cluster II reveal multiple interactions with neighboring residues (d) Highly diverse group of residues prone to variations in all SARS-CoV-2 sub lineages exhibit the capability to dramatically affect binding affinity. (e) Intermolecular interactions of shared mutations lying at RBD of all VoCs with neighboring residues and solvent during 300 ns MD simulations where (WAT) represents interactions with water molecules.

Figure 3

(a) RMSD of significant residues lying at RBD of all VoCs and WT are represented by box plots. (b) Snapshot of spike protein (green ribbon) exhibit positions of mutated residues lying at RBD which are directly involved in making interactions with ACE2 receptor (grey surface) (c) Comparative free binding energy profile of reported mutations lying at RBD (d) Comparative PCA of Delta and Omicron mutation T478K exhibit residual distribution along the subspace (e) Comparative PCA of Gamma, Delta and Omicron mutation E484/A/K exhibit residual distribution along the subspace.

Figure 4

(a) RMSD box plots of RBM of Delta, Omicron, and WT monomers (b) Snapshot of spike protein (green ribbon) exhibit the position of mutated residues at RBM critical for compact conformation of Omicron (c) Comparative free binding energy profile of reported mutations at RBM (d) Comparative RMSD box plots of mutated residues at fusion peptide site and HR1 along with insertion EPE lying at position 214 (e) PCA of monomer Delta exploit different energy minima while sampling trajectories (f) PCA of monomer Omicron sample in completely opposite direction compared to Delta monomer. (g) Comparative free binding energy profile of reported mutations at N-terminal, fusion peptide site, and HR1.

Figure 5

Conformational changes observed in different variants of spike protein during a simulation run. (a) WT trimer and (b) Omicron trimer, highlighting receptor in green and the three RBD domains in orange, red, and yellow. The ‘Up’ and ‘Down’ conformation of RBD is visible while interacting with the receptor and during no interaction, respectively. (c) and (d) zoomed-in view of the Delta and Omicron monomer respectively to display difference in structural compactness and stability. (e) Comparison of structural and conformational changes that occur during the binding of Delta and Omicron variants to ACE2 receptor. Zoomed in view of superimposed RBD domain and HR1 peptide where purple surface depicts L452R.

Figure 6

Intermolecular interactions surrounding the ins214EPE in the WT spike protein after 200 ns of the simulation run. (a) ACE2 receptor is in surf representation in green whereas the rest of the monomer is in ribbon representation (b) Zoomed in view of ins214EPE and interacting protein residues forming salt bridge and hydrogen bond interactions (c) Assessing the distribution of distances between residues involved in making salt bridges during MD simulations.

Figure 7

Intermolecular interactions surrounding the ins214EPE in the Omicron spike protein after 200 ns of the simulation run. (a) ACE2 receptor is in surf representation in green whereas the rest of the monomer is in ribbon representation (b) Zoomed in view of ins214EPE and interacting protein residues forming salt bridge and hydrogen bond interactions (c) Assessing the distribution of distances between residues involved in making salt bridges during MD simulations.

Figure 8

Monomers at 200 ns simulation run each. Insets representing the diverse structural shifts and altered angles formed (RBD-HR1-NTD) in the variants that were triggered by ACE2 binding. Orange ribbon displays the receptor.