Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Abstract

Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

Probing conformational landscapes of binding and allostery in the SARS-CoV-2 omicron variant complexes using microsecond atomistic simulations and perturbation-based profiling approaches: hidden role of omicron mutations as modulators of allosteric signaling and epistatic relationships

“…41 Atomic force microscopy (AFM) studies quantified the importance of mechanical stability in mediating immune evasion, showing that a combination of mechanical forces, protein stability, and binding interactions play an important role in controlling the virus's fitness advantage and immune escape mechanisms. 42–44…”

“…41 Atomic force microscopy (AFM) studies quantified the importance of mechanical stability in mediating immune evasion, showing that a combination of mechanical forces, protein stability, and binding interactions play an important role in controlling the virus's fitness advantage and immune escape mechanisms. [42][43][44] The Omicron BA.2 subvariants of SARS-CoV-2 have been associated with the increased transmissibility and vaccine evasion capacity. 45,46 Structural and biophysical studies of the RBD-ACE2 complexes for the BA.1.1, BA.2, and BA.3 variants revealed that the binding affinity of the Omicron BA.2 with ACE2 is stronger than the affinities of the BA.3 and BA.1 subvariants.…”

Interaction of SARS-CoV-2 with host cells and antibodies: experiment and simulation

“…The spike-ACE2 interface exploits a number of hydrogen bonds and salt brides stabilizing it and forming two strong flanks that can resist mechanical pulling. 88 In addition to protein contacts, the interface is flanked by both host and viral glycans. The ACE2 glycosylation at site N322 was suggested to increase the overall binding strength by binding to the RBD surface.…”

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

“…At the same time, Omicron mutations S477N, T478K, E484A and K417N may induce a moderate loss in ACE2 binding while promoting the increased neutralization escape potential of the Omicron variant from antibodies [41]. Atomic force microscopy studies revealed the role of mechanical stability in mediating immune evasion, pointing to a combined effect of mechanical forces, protein stability and binding interactions that collectively control the virus fitness advantage and immune escape mechanisms [42][43][44]. The structural basis of the higher binding affinity of ACE2 to currently circulating Omicron subvariants was elucidated in an investigation which reported the structures of the RBD-ACE2 complexes for BA.1.1, BA.2, and BA.3 variants [45].…”