Unravelling Specific Binding sites of Pulmonary Surfactants on Coronavirus Spike Protein Receptor-Binding Domain

The lung surfactant (LS) coating the alveoli is the first barrier to the airborne pathogens, such as coronaviruses, which may prevent lung infection. It is essential to understand the interactions of virion structural units with LS for efficient pharmaceutical design and formulation. Since LS is an inevitable encounter, both inhibitory as well as faciliatory interactions of the LS lipids with virion proteins and envelope play a crucial role in the virus’s fate in the respiratory system. In this work, by means of multiscale molecular dynamics simulations, we investigate the interactions of five LS lipids with the receptor binding domain (RBD) of the SARS-CoV2 Spike protein. By performing coarse-grained (CG) simulations of spontaneous protein-ligand binding, we identify six potential surfactant binding sites (SBS) on the RBD protein. We find that all surfactants bind to the binding pocket identified as the fatty acid binding site (FABS) that has allosteric effects on RBD-ACE2 binding. CG simulations reveal that FABS is most probable binding site for several phospholipids and cholesterol. Subsequent atomistic simulations of the back-transformed CG bound poses reveal high surfactant binding energies (27-58 kcal/mol) at FABS and surfactant-selective behavior of FABS-bound protein-surfactant complexes. Our analysis predicts that while anionic lipids POPG and POPI (palmitoyl oleoyl phosphatidyl glycerol/Inositol) may possess inhibitory effects, DPPC (dipalmitoyl phosphatidyl choline) and cholesterol may have facilitatory effects on the viral infection. Our simulations provide valuable guidance on pharmaceutical design and future research on corona virus pathology.