When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy.

Accurate determination of binding free energy is pivotal for the study of many biological processes and has been applied in a number of theoretical investigations to compare the affinity of severe acute respiratory syndrome coronavirus 2 variants toward the host cell. Diversity of these variants challenges the development of effective general therapies, their transmissibility relying either on an increased affinity toward their dedicated human receptor, the angiotensin-converting enzyme 2 (ACE2), or on escaping the immune response. Now that robust structural data are available, we have determined with utmost accuracy the standard binding free energy of the receptor-binding domain to the most widespread variants, namely, Alpha, Beta, Delta, and Omicron BA.2, as well as the wild type (WT) in complex either with ACE2 or with antibodies, namely, S2E12 and H11-D4, using a rigorous theoretical framework that combines molecular dynamics and potential-of-mean-force calculations. Our results show that an appropriate starting structure is crucial to ensure appropriate reproduction of the binding affinity, allowing the variants to be compared. They also emphasize the necessity to apply the relevant methodology, bereft of any shortcut, to account for all the contributions to the standard binding free energy. Our estimates of the binding affinities support the view that while the Alpha and Beta variants lean on an increased affinity toward the host cell, the Delta and Omicron BA.2 variants choose immune escape. Moreover, the S2E12 antibody, already known to be active against the WT (Starr et al., 2021; Mlcochova et al., 2021), proved to be equally effective against the Delta variant. In stark contrast, H11-D4 retains a low affinity toward the WT compared to that of ACE2 for the latter. Assuming robust structural information, the methodology employed herein successfully addresses the challenging protein-protein binding problem in the context of coronavirus disease 2019 while offering promising perspectives for predictive studies of ever-emerging variants.