Contact residue contributions to interaction energies between SARS-CoV-1 spike proteins and human ACE2 receptors.

Several viruses of the corona family interact, via their spike (S) proteins, with human cellular receptors. Spike proteins of SARS-CoV-1 and SARS-CoV-2 virions, being structurally related but not identical, mediate attachment to the human angiotensin-converting enzyme 2 (hACE2) receptor in similar but non-identical ways. Molecular-level understanding of interactions between spike proteins and hACE2 can aid strategies for blocking attachment of SARS-CoV-1, a potentially reemerging health threat, to human cells. We have identified dominant molecular-level interactions, some attractive and some repulsive, between the receptor binding domain of SARS-CoV-1 spike proteins (S-RBD) and hACE2. We performed fragment-based quantum-biochemical calculations which directly relate biomolecular structure to the hACE2...S-RBD interaction energy. Consistent with X-ray crystallography and cryo-EM, the interaction energy between hACE2 and S-RBD ([Formula: see text]26 kcal/mol) corresponds to a net intermolecular attraction which is significantly enhanced by inclusion of dispersion van der Waals forces. Protein fragments at the hACE2...S-RBD interface, that dominate host-virus attraction, have been identified together with their constituent amino acid residues. Two hACE2 fragments which include residues (GLU37, ASP38, TYR41, GLN42) and (GLU329, LYS353, GLY354), respectively, as well as three S-RBD fragments which include residues (TYR436), (ARG426) and (THR487, GLY488, TYR491), respectively, have been identified as primary attractors at the hACE2...S-RBD interface.

Attractive and repulsive residue fragments at the interface of SARS-CoV-2 and hACE2.

The initial stages of SARS-CoV-2 coronavirus attachment to human cells are mediated by non-covalent interactions of viral spike (S) protein receptor binding domains (S-RBD) with human ACE2 receptors (hACE2). Structural characterization techniques, such as X-ray crystallography (XRC) and cryoelectron microscopy (cryo-EM), previously identified SARS-CoV-2 spike protein conformations and their surface residues in contact with hACE2. However, recent quantum-biochemical calculations on the structurally related S-RBD of SARS-CoV-1 identified some contact-residue fragments as intrinsically attractive and others as repulsive. This indicates that not all surface residues are equally important for hACE2 attachment. Here, using similar quantum-biochemical methods, we report some four-residue fragments (i.e quartets) of the SARS-CoV-2 S-RBD as intrinsically attractive towards hACE2 and, therefore, directly promoting host-virus non-covalent binding. Other fragments are found to be repulsive although involved in intermolecular recognition. By evaluation of their respective intermolecular interaction energies we found two hACE2 fragments that include contact residues (ASP30, LYS31, HIS34) and (ASP38, TYR41, GLN42), respectively, behaving as important SARS-CoV-2 attractors. LYS353 also promotes viral binding via several mechanisms including dispersion van der Waals forces. Similarly, among others, three SARS-CoV-2 S-RBD fragments that include residues (GLN498, THR500, ASN501), (GLU484, PHE486, ASN487) and (LYS417), respectively, were identified as hACE2 attractors. In addition, key hACE2 quartets identified as weakly-repulsive towards the S-RBD of SARS-CoV-1 were found strongly attractive towards SARS-CoV-2 explaining, in part, the stronger binding affinity of hACE2 towards the latter coronavirus. These findings may guide the development of synthetic antibodies or identify potential viral epitopes.