MMGB/SA Consensus Estimate of the Binding Free Energy Between the Novel Coronavirus Spike Protein to the Human ACE2 Receptor

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 ΔGbind 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. Two estimates of ΔGbind are performed: 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 take the average of the resulting two ΔGbind values as the consensus estimate. For the well-studied Ras-Raf protein-protein complex, which has similar binding free energy to that of the SARS-CoV-2/ACE2 complex, the consensus ΔGbind = −11.8 ± 1 kcal/mol, vs. experimental −9.7 ± 0.2 kcal/mol.The consensus estimates for the SARS-CoV-2/ACE2 complex is ΔGbind = −9.4 ± 1.5 kcal/mol, which is in near quantitative agreement with experiment (−10.6 kcal/mol). The availability of a conceptually simple MMGB/SA-based protocol for analysis of the SARS-CoV-2 /ACE2 binding may be beneficial in light of the need to move forward fast.

An Effective MM/GBSA Protocol for Absolute Binding Free Energy Calculations: A Case Study on SARS-CoV-2 Spike Protein and the Human ACE2 Receptor

“…Human H-Ras and the Ras-binding domain of C-Raf1, the so-called Ras–Raf complex [ 8 , 28 ], is chosen as the reference for the initial evaluation of the MM/GBSA model. As a new extension to our previous works [ 45 , 46 ], a novel truncation strategy is introduced and tested on Ras–Raf and SARS-CoV-2 S RBD/ACE2. Through this strategy, the truncated structure will be one connected component that is biologically more interpretable than the standard truncation methods.…”

Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

“…K-Ras at membrane), 30,31 the nature of the Spike protein: Nrp1 complex suggests that several binding interfaces can interconvert in their use and their occupancies can be transient. The latter is also reflected, in comparison to reports of the SARS-CoV-2 RBD: ACE2 interaction energy 32 in wider variation of atom-atom pairwise interaction energies between Nrp1 a2-b1-b2 and the Spike protein, as well as the complex-buried area of the accessible surface between the models. A full analysis of the energy landscape and estimation of free energies of binding is a computationally exhaustive endeavor and beyond the scope of this report.…”

Coinfection and Interference Phenomena Are the Results of Multiple Thermodynamic Competitive Interactions

“…First, in order to infect a cell, a virus must enter through the cell membrane. The attachment of the virus to the membrane receptor, or the susceptibility [61], is quantified by the Gibbs energy of binding, influencing the binding rate, as will be discussed below [27,[32][33][34]40,46,62]. Once the virus enters the cytoplasm, it performs disassembly, a process that is the opposite of self-assembly.…”

“…Thus, the Gibbs energy of growth can be used to quantify the interaction of viruses in the host cell cytoplasm. Similarly, the rate of virus attachment to the host cell, rb, can be quantified by the Gibbs energy of binding, ΔbG [27,[32][33][34]40,46,62], according to the linear phenomenological equation [63,64]. At the molecular level, a more negative Gibbs energy of binding implies stronger attachment of the virus to the receptor, which in turn implies more efficient entrance into the cell [26,40,46].…”

“…The virus enters the host cell by binding to a specific receptor [15]. This is a virushost interaction that takes place at the cell surface, which can be quantified by the Gibbs energy of binding [27,[32][33][34]. Once inside the cell, the virus interacts with it in the cytoplasm, hijacking the biosynthetic pathways of the host cell [9,11,35].…”