In Silico Comparison of SP-A and ACE2 Binding to the SARS-CoV-2 Spike Protein Using Quantum Computing

Abstract

Rationale: The pulmonary surfactant protein A (SP-A) plays an immune protective role by binding to the cell membrane of immune cells and by opsonizing infectious agents such as bacteria, fungi and viruses through glycoprotein and lipid binding domains. SARS-CoV-2 enters airway epithelial cells through its Spike glycoprotein (S protein) that binds the Angiotensin Converting Enzyme 2 (ACE2) on the cell surface. Using in silico methods we aimed to predict whether human SP-A could bind the S protein and whether this could interfere with SARS-CoV-2 - ACE2 binding. Methods: We assessed binding sites, the relative binding affinity of the interactions, and the protein chains and residues involved using ZDOCK and a novel software “Polar+” .We then compared these binding parameters between S protein - ACE2 and S protein-SP-A binding. We hypothesized that SP-A competes for the same binding site of the S protein with ACE2. We applied the “Polar+” to determine the best binding sites between the proteins.This process involved electronegativity and topologically oriented molecular pruning, calculation of electronic force-fields and electrostatic binding combined with protein-protein docking, geometric fitting and assessment of protein glycosylation sites. Results: We established the parameters of ACE2-S protein binding (left panel in figure) and found that SP-A potentially binds to the S protein with an affinity similar to that of ACE2. However, our data suggested that SP-A most likely binds to the fusion portion of the S2 chain of the S protein. This part is responsible for viral entry into the host cell (right panel in figure). Conclusions: Our study supports the use of quantum computing and the Polar+ algorithm for studying protein-protein interactions. Based on our findings we speculate that SP-A while does not compete with ACE2 for S protein binding, could still interfere with viral entry to the cell through hindering the membrane fusion process. These findings are important in understanding SARS-CoV-2 biology and warrant studies in experimental biological systems.