Critical interactions for SARS-CoV-2 spike protein binding to ACE2 identified by machine learning

Abstract

Both SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor. Based on high-resolution structures, the two viruses bind in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Here we have used molecular dynamics (MD) simulations, machine learning (ML), and free energy perturbation (FEP) calculations to elucidate the differences in RBD binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.

Best Practices in Constant pH MD Simulations: Accuracy and Sampling

“…We, therefore, analyzed the distributions of the dihedral angles in the side chains of titratable amino acids in the publicly available trajectories of G-protein coupled receptors and of SARS-CoV-2 proteins. 56,57 The distributions of these dihedral angles, plotted in Figure 2A, reflect the shape of the underlying torsion potentials with maxima coinciding with local minima of the potential profiles. The low density near barriers suggests that these barriers are rather high and might be reduced without affecting the dihedral distributions.…”

“…Distributions of side chain dihedral angles in proteins were derived from publicly shared MD trajectories of proteins with PDB IDs: 1U19, 52 2RH1, 53 2Y02 54 and 5UEN 55 obtained from the GPCRMD, 56 and the SARS-CoV-2 databases (https://covid.molssi.org/). 57 For each trajectory, the distributions of the following dihedral angles were calculated:…”

Free energy perturbation calculations of mutation effects on SARS-CoV-2 RBD::ACE2 binding affinity

“…Here we explore the ability of FEP calculations to reproduce the effects of mutations on the binding of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein with the human angiotensin converting enzyme 2 (ACE2) using the FEP+ implementation (see Methods). Given that the pathogen entry into the host cell is mediated by RBD::ACE2 binding, the problem has attracted considerable interest and multiple experimental and computations studies (33,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63) have been reported. We chose to study a set of 23 frequently observed RBD mutations (Table S1) located in the RBD::ACE2 interface (Fig.…”

Point mutations in SARS-CoV-2 variants induce long-range dynamical perturbations in neutralizing antibodies

“…To address this urgent crisis, a number of computational studies have been performed to obtain a molecular level understanding of the effect of mutations in the RBD on its binding with the hACE2 receptor and antibodies. [43][44][45][46][47][48][49] A recent work, specically explored the change in binding free energy and molecular interactions between spike RBD and a range of neutralizing nanobodies and monoclonal antibodies. 50 Taken collectively, these studies revealed that the residues which got mutated in the variants of concern can play an important role in antibody binding.…”