Binding Free Energy of the Novel Coronavirus Spike Protein and the Human ACE2 Receptor: An MMGB/SA Computational Study

Abstract

The ability to estimate protein-protein binding free energy in a computationally efficient via a physics-based approach is beneficial to research focused on the mechanism of viruses binding to their target proteins. Implicit solvation methodology may be particularly useful in the early stages of such research, as it can offer valuable insights into the binding process, quickly. Here we evaluate the potential of the related molecular mechanics generalized Born surface area (MMGB/SA) approach to estimate the binding free energy between the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor. The calculations are based on a recent flavor of the generalized Born model, GBNSR6, shown to be effective in protein-ligand binding estimates, but never before used in the MMGB/SA context. Two options for representing the dielectric boundary of the molecule are evaluated: one based on standard bondi radii, and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein-ligand binding. We first test the entire computational pipeline on the well-studied Ras-Raf protein-protein complex, which has similar binding free energy to that of the SARS-CoV-2/ACE2 complex. Predictions based on both radii sets are closer to experiment compared to a previously published estimate based on MMGB/SA. The two estimates for the SARS-CoV-2/ACE2 also provide a "bound" on the experimental ΔGbind: --14.7 (bondi) < -10.6(Exp.) < -4.1(OPT1) kcal/mol. Both estimates point to the expected near cancellation of the relatively large enthalpy and entropy contributions, suggesting that the proposed MMGB/SA protocol may be trustworthy, at least qualitatively, for analysis of the SARS-CoV-2/ACE2 in light of the need to move forward fast.