The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor

Esther S. Brielle; Dina Schneidman-Duhovny; Michal Linial

We investigate the dynamics of a designed SARS (SARS-des) variant (11) Table S1 ). The L486F mutation is of special interest for the COVID-19 RBD as well because it has this same substitution. Our MD simulation analysis reveals that the SARS-des has a substantially lower interaction scores with ACE2 (median of -2199.2, Fig. S2) , as expected for an optimized human ACE2-binding RBD design. We observed that these two mutations not only enhance the binding affinity to ACE2, but also lead to a substantial stabilization of the interaction interface. The fluctuation signatures along the RBD of SARS-des are surprisingly similar to those recorded for COVID-19 (Fig. 3, B and C) . Thus, the switch from a flexible binding mode (for SARS-2002) to a stable one (COVID-19 and SARSdes, Fig. 3B ) highlights the remarkable capacity of the RBD to adopt alternative receptor binding strategies driven by a minimal number of amino acid substitutions. This analysis reveals the critical role of L486F (SARS-des residue F472) for stabilizing the COVID-19-ACE2 interface and a reduction in the number of states of the COVID-19 spike protein bound to an ACE2 receptor.