Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies

Abstract

SARS-CoV-2 has caused immeasurable damage worldwide and available treatments with high efficacy are still scarce. With the continuous emergence of new variants of the virus, such as Omicron, Alpha, Beta, Gamma, and Delta -the so-called variants of concern, the available therapeutic and prevention strategies had to return to the experimental trial to verify their effectiveness against them. This work aims to expand the knowledge about the SARS-CoV-2 receptor-binding domain (RBD) interactions with cell receptors and monoclonal antibodies (mAbs). Special attention is given to the Omicron variant and its comparison with the others, including its sublineage BA.2 and two new ones (B.1.640.1 and B.1.640.2/IHU) recently found in France. By using constant-pH Monte Carlo simulations, the free energy of interactions between the SARS-CoV-2 receptor-binding domain (RBD) from different variants and several partners (Angiotensin-Converting Enzyme-2 (ACE2) polymorphisms and several mAbs) were calculated. It was evaluated both the impact of mutations for the RBD-ACE2 and how strongly each of mAb can bind to the virus RBD, which can indicate their therapeutic potential for neutralization. RBD-ACE2-binding affinities were higher for two ACE2 polymorphisms typically found in Europeans (rs142984500 and rs4646116), indicating that these types of polymorphisms may be related to genetic susceptibility to COVID-19. The antibody landscape was computationally investigated with the largest set of mAbs so far in the literature. From the 33 studied binders, groups of mAbs were identified with weak (e.g. S110 and Ab3b4), medium (e.g. CR3022), and strong binding affinities (e.g. P01'' ', S2K146 and S230). All the mAbs with strong binding capacity could also bind to the RBD from SARS-CoV-1, SARS-CoV-2 wt, and all studied variants. These mAbs and especially their combination are amenable to experimentation and clinical trials because of their high binding affinities and neutralization potential for current known virus mutations and a universal coronavirus.

Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

“…Comparisons of the binding affinities for the VOCs with other theoretical studies were reported by us in previous work. 11 For example, Golcuk and coauthors 52 recently also showed that the RBD-ACE2 binding affinity is strengthened for the Delta in comparison with the wt as seen by us. In their work, they identified an additional contribution from increased hydrophobic interactions.…”

“…119 The latter issue has been recently discussed in the literature. 11,64,119 On one hand, the model can capture larger discrepancies between different variants as for the comparison between Delta and Omicron/BA.1. On the other hand, differences for a single mutation can be within the estimated statistical error even when the reported experimental assays show a larger enhancement for the binding affinity.…”

“…This would correspond to the S protein being all the time at the "up" conformational state. 6,11,32 The simulated model does not incorporate the transition between the "up/down" states of the S protein. Only the RBD of the S protein is present in the simulations.…”

“…Other details, justifications, validation, pros, and cons are given elsewhere. 5,6,11,22,85,87 In short, the full configurational energy of the system [U({r k })] combining a screened Coulombic term (first term) with an LJ one (second term) is given by Titratable residues are highlighted in bold. VOCs and VOIs are, respectively, the "variants of concern" (mutations that are circulating more than others, causing more severe disease, or are more transmissible) and "variants of interest" (mutations that are circulating more than others with a risk to be upgraded to a VOC) as classified by the World Health Organization.…”

“…9 K B T (K B is the Boltzmann constant) for amino acid pairs. 6,85,87 Following the previous works, 6,11,32 the coordinates of the ACE2 molecule were obtained from the PDB id 2AJF (chain A, resolution 2.9 Å, pH 7.5). The SARS-CoV-2 RBD (wt) coordinates were taken from ref 6 to allow a proper comparison with recent studies.…”