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

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

To investigate the dynamics of COVID-19 binding compared to SARS-2002, we calculate the root-mean-square fluctuation (RMSF) of each residue with respect to the lowest energy snapshot from their respective 100ns MD simulation trajectory. The interface region in the RBD contains two loops (loop1: residues 474-489, loop2: residues 498-505; using COVID-19 numbering, Fig. 3D ) that bind to the ACE2 N-terminal helix on both of its ends. These two loops are highly flexible in the SARS-2002 RBD (Fig. 3, A and D) . While loop1 is also fluctuating in the COVID-19 RBD, albeit much less, loop2 remains relatively rigid in the COVID-19 RBD. In addition, we find that in the COVID-19-RBD, a region centered around K417 leads to further stability relative to the corresponding region in SARS-2002. We attribute this difference to the unique interaction of COVID-19 at position K417 with the middle of the N-terminal ACE2 helix, thus serving as an anchor site to the receptor (Fig. 2C and Fig. 3A) . The contribution of K417 to ACE2 binding is observed in a recent cryoEM structure of the COVID-19 spike protein bound to ACE2 (17) . Overall, COVID-19 is more rigid compared to SARS-2002 (Fig. 3, A and D) .