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

Abstract

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 ($$\approx -$$ ≈ - 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 former, a potentially reemerging pathogen 5 , 6 , initiated an infectious outbreak in late 2002 whereas the latter is responsible for the current worldwide pandemic. It has been realized that specific structural differences between surface proteins of each coronavirus requires, also specific, investigation of the binding mechanism of each virus to host human cells 7 . As such, molecular-level understanding of the binding mechanisms of each coronavirus, such as SARS-CoV-1 or SARS-CoV-2, to human cells is important for developing effective countermeasures including antiviral drugs and vaccines.…”

“…Some studies, including ab initio fragment molecular orbital (FMO) calculations 21 , identified individual residues considered important for intermolecular recognition and binding at the hACE2...S-RBD interface. An alternative methodology, implemented in the context of fragment-based quantum-biochemical calculations 7 , provides complementary insight about host-virus interactions and specifies the neutral, attractive or repulsive nature of particular hACE2 and S-RBD fragments . The method combines density functional calculations with van der Waals dispersion contributions 22 to establish a relationship between the molecular structure of host-virus interface fragments and their corresponding, attractive or repulsive, interaction energies 7 .…”

“…An alternative methodology, implemented in the context of fragment-based quantum-biochemical calculations 7 , provides complementary insight about host-virus interactions and specifies the neutral, attractive or repulsive nature of particular hACE2 and S-RBD fragments . The method combines density functional calculations with van der Waals dispersion contributions 22 to establish a relationship between the molecular structure of host-virus interface fragments and their corresponding, attractive or repulsive, interaction energies 7 . Here we used this fragment-based approach with two recent XRC structures of the SARS-CoV-2 spike protein in complex with hACE2 14 , 15 .…”

“…For the hACE2...SARS-CoV-1 complex, contact residue fragments, some of attractive character and some of repulsive nature, were recently identified by means of fragment-based quantum-biochemical calculations 7 . Here, we proceed in a similar fashion to identify residue fragments, at the hACE2...SARS-CoV-2 interface, and determine their attractive or repulsive nature.…”

“…A previous study characterized the hACE2...SARS-CoV-1 interface and determined which four-residue fragments (i.e. quartets ) are most attractive or most repulsive 7 . It was determined that two hACE2-centered quartets and three S-RBD-centered quartets are mainly responsible for the attractive interaction of the SARS-CoV-1 S-RBD with hACE2.…”