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Effects of Variants of Concern Mutations on the Force-Stability of the SARS-CoV-2:ACE2 Interface and Virus Transmissibility
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Effects of Variants of Concern Mutations on the Force-Stability of the SARS-CoV-2:ACE2 Interface and Virus Transmissibility
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Effects of Variants of Concern Mutations on the Force-Stability of the SARS-CoV-2:ACE2 Interface and Virus Transmissibility
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Paper
Effects of Variants of Concern Mutations on the Force-Stability of the SARS-CoV-2:ACE2 Interface and Virus Transmissibility
2023
Overview
Viruses mutate under a variety of selection pressures, allowing them to continuously adapt to their hosts. Mutations in SARS-CoV-2 have shown effective evasion of population immunity and increased affinity to host factors, in particular to the cellular receptor ACE2. In the dynamic environment of the respiratory tract, the question arises, if not only affinity, but also force-stability of the SARS-CoV-2:ACE2 bond, initiating infection of host cells, might be a selection factor for mutations. Here, we use magnetic tweezers (MT) to study the effect of amino acid substitutions in variants of concern (VOCs) on RBD:ACE2 bond kinetics with and without external load using a previously established assay. Matching bulk-affinity measurements determined in literature, we find higher affinity for all VOCs compared to wt. In contrast to that, Alpha is the only VOC markedly different from the wild type showing higher mechanical resilience under force. Investigating the RBD:ACE2 interactions with molecular dynamics simulations, we were able to rationalize the mechanistic molecular origins of this increase in force-stability. Our study emphasizes the diversity of contributions to the assertiveness of variants and establishes force-stability as one of several factors for fitness. Understanding fitness-advantages opens the possibility for prediction of likely mutations allowing rapid adjustment of therapeutics, vaccination, and intervention measures.Competing Interest StatementThe authors have declared no competing interest.
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
