Infection of human cells by the SARS-CoV2 relies on its binding to a specific receptor and subsequent fusion of the viral and host-cell membranes. The fusion peptide (FP), a short peptide segment in the spike protein, plays a central role in this process by inserting into the host cell membrane, thereby initiating the fusion of the two membranes. Here, we use a large array of all-atom molecular dynamics (MD) simulations using our accelerated membrane model, the Highly Mobile Membrane Mimetic (HMMM), to investigate the interaction of the SARS-CoV2 FP with a lipid bilayer representing mammalian cellular membranes, and to characterize the membrane-inserted form of the peptide. Several independent initial systems with diverse initial positioning and orientation of the FP with respect to the membrane and randomized lipid mixings were generated. Each system was simulated as multiple independent replicas. The majority of the simulations capture stable membrane binding of the FP. Clustering of the results reveals three major membrane binding modes, from which one is the most representative binding mode. The resulting membrane-bound mode shows a deep penetration of the FP into the membrane accompanied by extension of the helical structure of the peptide. This mode substantiates the results of biochemical studies on amino acids involved in the interaction of the FP with cellular membranes. Taken together, the results shed light on a key step involved in SARS-CoV2 infection with potential implications for designing novel inhibitors.

Binding mode of SARS-CoV2 fusion peptide to human cellular membrane

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.