Omicron Spike Protein Has a Positive Electrostatic Surface That Promotes ACE2 Recognition and Antibody Escape

Abstract

High transmissibility is a hallmark of the Omicron variant of SARS-CoV-2. Understanding the molecular determinants of Omicron’s transmissibility will impact development of intervention strategies. Here we map the electrostatic potential surface of the Spike protein to show that major SARS-CoV-2 variants have accumulated positive charges in solvent-exposed regions of the Spike protein, especially its ACE2-binding interface. Significantly, the Omicron Spike-ACE2 complex has complementary electrostatic surfaces. In contrast, interfaces between Omicron and neutralizing antibodies tend to have similar positively charged surfaces. Structural modeling demonstrates that the electrostatic property of Omicron’s Spike receptor binding domain (S RBD) plays a role in enhancing ACE2 recognition and destabilizing Spike-antibody complexes. Specifically, the Omicron S RBD has favorable electrostatic interaction energy with ACE2 that is 3-5 times greater than the Delta variant over a range of 20 Å, implying efficient recognition of host receptors. Computed binding affinities of six representative S RBD-antibody complexes show that Omicron can escape most antibodies targeting the ACE2-binding region of S RBD. Interestingly, a straightforward assessment of the electrostatic surfaces of 18 neutralizing antibodies correctly predicted the Omicron escape status of 80% of cases. Collectively, our structural analysis implies that Omicron S RBD interaction interfaces have been optimized to simultaneously promote access to human ACE2 receptors and evade antibodies. These findings suggest that electrostatic interactions are a major contributing factor for increased Omicron transmissibility relative to other variants.

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

“…Indeed, according to the experiments [ 51 , 52 ], the escaping mutations for the studied ultrapotent antibodies can emerge in the charged positions K444 and R493 of the S-RBD Omicron, causing a modest ~5–7-fold decrease in neutralization, attributed to only partially optimized electrostatic contacts. Consistent with the related studies [ 109 , 110 , 111 , 112 ], our analysis similarly indicated that potent antibodies against S-RBD Omicron should be enriched with negatively charged residues in positions interacting with the Omicron positively charged mutational sites. At the same time, a far more significant increase was seen in the number of hydrophobic contacts in the S-RBD and S-RBD Omicron complexes with the synergistic antibody pairs ( Table 2 ).…”

“…Our analysis supports the notion that the electrostatic interactions could play an important stabilizing role in the S-RBD complexes with ultrapotent antibodies [ 109 , 110 ]. Recent quantitative assessment of the antibody escape showed that the S-RBD Omicron variant can be resistant to most neutralizing antibodies, primarily due to either unfavorable or only partly optimized electrostatic interactions [ 111 , 112 ]. Indeed, according to the experiments [ 51 , 52 ], the escaping mutations for the studied ultrapotent antibodies can emerge in the charged positions K444 and R493 of the S-RBD Omicron, causing a modest ~5–7-fold decrease in neutralization, attributed to only partially optimized electrostatic contacts.…”

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

“…35 Similar results and analysis at pH 7 are found in the recent paper by Gan and colleagues using the Poisson-Boltzmann approach (except for BA.4 and BA.5 which were not included in their study). 62 The order of the computed isoelectric points (pI) is wt, Alpha (8.6) < Beta, Gamma (8.9) < Delta, Omicron, BA.2, BA.2.12.1, BA. from calculations using the ab initio fragment molecular orbital method (<Z (RBDwt) >=+2 and <Z (ACE2) >=-24).…”

“…23 Other results that became available after this comparison also report the same trends. 61,62 For the recent variants from the Omicron family, no data is yet available at the moment of writing this work.…”

“…56 There is undoubtedly well-built support for the importance of electrostatic interactions for this process which is constantly confirmed for the latest variants, ACE2 polymorphisms, and new studied Abs. 23,32,36,[57][58][59][60][61][62] Nevertheless, it is worth mentioning that Jawad and co-authors more recently added that the van der Waals interactions can also be critical to stabilizing the RBD-ACE2 complex even if the Coulombic interactions are the main driving force for the recognition process between the RBD and ACE2. 59 Although the main aspects are consistently reproduced, quantitative results for the predicted binding affinities can vary a lot as was critically discussed by Taka and colleagues.…”