Adsorption of pulmonary and exogeneous surfactants on SARS-CoV-2 spike protein

Abstract

COVID-19 is transmitted by airborne particles containing virions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus virions represent nanoparticles enveloped by a lipid bilayer decorated by a "crown" of Spike protein protrusions. Virus transmission into the cells is induced by binding of Spike proteins with ACE2 receptors of alveolar epithelial cells. Active clinical search is ongoing for exogenous surfactants and biologically active chemicals capable of hindering virion-receptor binding. Here, we explore by using coarse-grained molecular dynamics simulations the physico-chemical mechanisms of adsorption of selected pulmonary surfactants, zwitterionic dipalmitoyl phosphatidyl choline and cholesterol, and exogeneous anionic surfactant, sodium dodecyl sulfate, on the S1-domain of the Spike protein. We show that surfactants form micellar aggregates that selectively adhere to the specific regions of the S1-domain that are responsible for binding with ACE2 receptors. We find distinctly higher cholesterol adsorption and stronger cholesterol-S1 interactions in comparison with other surfactants, that is consistent with the experimental observations of the effects of cholesterol on COVID-19 infection. Distribution of adsorbed surfactant along the protein residue chain is highly specific and inhomogeneous with preferential adsorption around specific amino acid sequences. We observe preferential adsorption of surfactants on cationic arginine and lysine residues in the receptor-binding domain (RBD) that play an important role in ACE2 binding and are present in higher amounts in Delta and Omicron variants, which may lead to blocking direct Spike-ACE2 interactions. Our findings of strong selective adhesion of surfactant aggregates to Spike proteins have important implications for informing clinical search for therapeutic surfactants for curing and preventing COVID-19 caused by SARS-CoV-2 and its variants.

Keywords: Coarse-grained simulations; Coronavirus virions; Molecular dynamics; Protein-surfactant interactions; Surfactant adsorption; Surfactant therapy.