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Single-molecule force stability of the SARS-CoV-2–ACE2 interface in variants-of-concern

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Citation

Bauer, M. S., Gruber, S., Hausch, A., Melo, M. C. R., Gomes, P. S. F. C., Nicolaus, T., et al. (2024). Single-molecule force stability of the SARS-CoV-2–ACE2 interface in variants-of-concern. Nature Nanotechnology, 19(3), 399-405. doi:10.1038/s41565-023-01536-7.


Cite as: https://hdl.handle.net/21.11116/0000-000F-8344-0
Abstract
Mutations in SARS-CoV-2 have shown effective evasion of population immunity and increased affinity to the cellular receptor angiotensin-converting enzyme 2 (ACE2). However, in the dynamic environment of the respiratory tract, forces act on the binding partners, which raises the question of whether not only affinity but also force stability of the SARS-CoV-2–ACE2 interaction might be a selection factor for mutations. Using magnetic tweezers, we investigate the impact of amino acid substitutions in variants of concern (Alpha, Beta, Gamma and Delta) and on force-stability and bond kinetic of the receptor-binding domain–ACE2 interface at a single-molecule resolution. We find a higher affinity for all of the variants of concern (>fivefold) compared with the wild type. In contrast, Alpha is the only variant of concern that shows higher force stability (by 17%) compared with the wild type. Using molecular dynamics simulations, we rationalize the mechanistic molecular origins of this increase in force stability. Our study emphasizes the diversity of contributions to the transmissibility of variants and establishes force stability as one of the several factors for fitness. Understanding fitness advantages opens the possibility for the prediction of probable mutations, allowing a rapid adjustment of therapeutics, vaccines and intervention measures.