ABSTRACT
A remarkable number of SARS-CoV-2 variants and other as yet unmonitored lineages harbor amino-acid substitutions with the potential to modulate the interface between the spike receptor-binding domain (RBD) and its receptor ACE2. The naturally occurring Q498Y substitution, which is present in currently circulating SARS-CoV-2 variants, has drawn the attention of several investigations. While computational predictions and in vitro binding studies suggest that Q498Y increases the binding affinity of the spike protein for ACE2, experimental in vivo models of infection have shown that a triple mutant carrying the Q498Y replacement is fatal in mice. To accurately characterize the binding kinetics of the RBD Q498Y-ACE2 interaction, biolayer interferometry analyses were performed. A significant enhancement of the RBD-ACE2 binding affinity relative to a reference SARS-CoV-2 variant of concern carrying three simultaneous replacements was observed. In addition, the RBD Q498Y mutant bound to ACE2 was crystallized. Compared with the structure of its wild-type counterpart, the RBD Q498Y-ACE2 complex reveals the conservation of major hydrogen-bond interactions and a more populated, nonpolar set of contacts mediated by the bulky side chain of Tyr498 that collectively lead to this increase in binding affinity. In summary, these studies contribute to a deeper understanding of the impact of a relevant mutation present in currently circulating SARS-CoV-2 variants which might lead to stronger host-pathogen interactions.
Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , Binding Sites , Humans , Mice , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding/genetics , Spike Glycoprotein, Coronavirus/chemistryABSTRACT
A previously developed mechanistic model of COVID-19 transmission has been adapted and applied here to study the evolution of the disease and the effect of intervention measures in some European countries and territories where the disease has had a major impact. A clear impact of the major intervention measures on the reproduction number (Rt) has been found in all studied countries and territories, as already suggested by the drop in the number of deaths over time. Interestingly, the impact of such major intervention measures seems to be the same in most of these countries. The model has also provided realistic estimates of the total number of infections, active cases and future outcomes. While the predictive capabilities of the model are much more uncertain before the peak of the outbreak, we could still reliably predict the evolution of the disease after a major intervention by assuming the subsequent reproduction number from the current study. A greater challenge is to foresee the long-term impact of softer intervention measures, but this model can estimate the outcome of different scenarios and help to plan changes for the implementation of control measures in a given country or region.