Omicron Coronavirus: pH-Dependent Electrostatic Potential and Energy of Association of Spike Protein to ACE2 Receptor

Abstract

The association of the S-protein of the SARS-CoV-2 beta coronavirus to ACE2 receptors of the human epithelial cells determines its contagiousness and pathogenicity. We computed the pH-dependent electric potential on the surface of the interacting globular proteins and pH-dependent Gibbs free energy at the association of the wild-type strain and the omicron variant. The calculated isoelectric points of the ACE2 receptor (pI 5.4) and the S-protein in trimeric form (pI 7.3, wild type), (pI 7.8, omicron variant), experimentally verified by isoelectric focusing, show that at pH 6–7, the S1–ACE2 association is conditioned by electrostatic attraction of the oppositely charged receptor and viral protein. The comparison of the local electrostatic potentials of the omicron variant and the wild-type strain shows that the point mutations alter the electrostatic potential in a relatively small area on the surface of the receptor-binding domain (RBD) of the S1 subunit. The appearance of seven charge-changing point mutations in RBD (equivalent to three additional positive charges) leads to a stronger S1–ACE2 association at pH 5.5 (typical for the respiratory tract) and a weaker one at pH 7.4 (characteristic of the blood plasma); this reveals the reason for the higher contagiousness but lower pathogenicity of the omicron variant in comparison to the wild-type strain.

AlphaFold2 Predictions of Conformational Ensembles and Atomistic Simulations of the SARS-CoV-2 Spike XBB Lineages Reveal Epistatic Couplings between Convergent Mutational Hotspots that Control ACE2 Affinity

“…The significant contribution of these residues is determined by strong electrostatic interactions mediated by multiple lysine residues, leading to the accumulation of positively charged substitutions interacting with the negatively charged ACE2 binding interface. Recent studies showed accumulation of positive charges at the ACE2-binding interface of Omicron variants, suggesting a critical role of electrostatic interactions in driving the enhanced affinity of the Omicron S-ACE2 complexes. − …”

AlphaFold2-Enabled Atomistic Modeling of Epistatic Binding Mechanisms for the SARS-CoV-2 Spike Omicron XBB.1.5, EG.5 and FLip Variants: Convergent Evolution Hotspots Cooperate to Control Stability and Conformational Adaptability in Balancing ACE2 Binding and Antibody Resistance

“…130,131 Extensive simulations investigated the electrostatic features of the RBD for the several S variants and binding affinities at several pH regimes revealing that the virus evolution may primarily exploit the electrostatic forces to make RBD more positively charged and improve the RBD-ACE2 binding affinity. 132 It is possible that evolution of the electrostatic RBD surface in XBB Omicron variants may be exploited to enable both the incremental improvements in the ACE2 binding and resistance to antibody interactions. Of particular interest are the binding affinity contributions of L455, F456 in XBB.1.5 and their respective mutants F455/L456 in the XBB.1.5 FLip variant (Figure 11).…”

Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling

“…73 Extensive simulations investigated the electrostatic features of the RBD for the several S variants, their main physical–chemical properties and binding affinities at several pH regimes revealing that the virus evolution may primarily exploit the electrostatic forces to make RBD more positively charged and improve the RBD-ACE2 binding affinity and transmission. 75…”

“…71 A significant number of computational studies emphasized the role of electrostatic interactions as a dominant thermodynamic force leading at binding of the S-protein with the ACE2 receptor and antibodies. [72][73][74][75] Recent studies mapped the electrostatic potential surface of S protein and major variants to show accumulated positive charges at the ACE2-binding interface, revealing the critical role of complementary electrostatic interactions driving the enhanced affinity the Omicron S-ACE2 complexes. 73 Extensive simulations investigated the electrostatic features of the RBD for the several S variants, their main physical-chemical properties and binding affinities at several pH regimes revealing that the virus evolution may primarily exploit the electrostatic forces to make RBD more positively charged and improve the RBD-ACE2 binding affinity and transmission.…”

“…73 Extensive simulations investigated the electrostatic features of the RBD for the several S variants, their main physical-chemical properties and binding affinities at several pH regimes revealing that the virus evolution may primarily exploit the electrostatic forces to make RBD more positively charged and improve the RBD-ACE2 binding affinity and transmission. 75 The recent structural and computational studies suggested that Omicron mutations have significant and often variant-specific effect on mediating conformational dynamics changes in the S protein including allosterically induced plasticity at the remote regions leading to the formation and evolution of druggable cryptic pockets. 76,77 Evolutionary trajectories of Omicron lineages proceeded through diverse mechanisms including but not limited to simple and complex recombination, antigenic drift and convergent evolution that led to convergent immune-escape mutations and effective evasion of neutralizing antibodies.…”