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

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

The COVID-19 RBD (residues 319-529) shares a 72.8% sequence identity and high structural similarity with the SARS-2002 RBD ( Table 1 ). In contrast, the RBD of HCoV-NL63 is only 17.1% identical to that of COVID-19 and there are no significant structural similarities between them (Fig. S1) . Remarkably, the RBD of MERS-CoV, which is structurally similar to that of COVID-19 (20.1% sequence identity, 65% structure similarity) recognizes a different host receptor (DPP4) for its cell entry and does not bind ACE2 (14) . We ran 100ns molecular dynamic (MD) simulations of ACE2 in complex with the RBDs of the COVID-19, SARS-2002, and HCoV-NL63 viruses to quantify the energetics and the dynamics of the different RBD-ACE2 interactions. The simulation trajectory snapshots at 10 ps intervals (10,000 frames) were analyzed by a statistical potential to assess the probability of the RBD-ACE2 interaction (SOAP score, (16)), with lower values corresponding to higher probabilities and thus higher affinities. The interaction scores for COVID-19 RBD-ACE2 were comparable to those of SARS-2002, median of -1865.9 and -1929.5, respectively (Fig. 1A) . HCoV-NL63 has RBD-ACE2 interaction scores are higher than both of the SARS-CoVs (median of -941.6). MERS, which is structurally similar to COVID-19 (Table 1) does not bind ACE2. MERS virus which binds dipeptidyl peptidase-4 (DPP4, also known as CD26 (14)), has RBD-ACE2 interaction scores that indicate extremely weak affinity (median of -692.6), as expected from a non-cognate receptor interaction. COVID-19 has the largest buried surface area at the interface (1204Ã… 2 ), followed by the interface area for SARS-2002 (998Ã… 2 ) and HCoV-NL63 (973Ã… 2 ). The number of ACE2 contacting residues maintains the same order, with 30, 24, and 23 for COVID-19, SARS-2002, and HCoV-NL63, respectively (Fig. 1C) . The three RBDs exploit specific binding sites on ACE2 based on the analysis of the MD trajectories ( Fig. 1 , C and D; Movie S1). There is a significant overlap of ACE2 interacting residues between COVID-19 and SARS-2002 (at least 73%), while HCoV-NL63 shares only 17% and 36% of contacts with SARS-2002 and COVID-19, respectively. These findings suggest that the coronaviruses exert different interaction strategies with their cognate receptors to achieve the affinity that is required for effective cell entry. An ACE2 residue is considered as part of the interface if one of its atoms is within 4Ã… from any RBD atom in at least 10% of the 10,000 MD simulation frames. (D) Overlay of 50 snapshots for each of the three RBDs. The ACE2 is in surface representation (gray). The frames were aligned using the N-terminal fragment of ACE2 that contains the two helices participating in the RBDs binding.