Insights into the self-assembly and interaction of sars-cov-2 fusion peptides with biomimetic plasma membranes

Abstract

First identified in late 2019, the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, rapidly escalated into a global health crisis. SARS-CoV-2 is a single-stranded RNA virus encased in a lipid envelope that houses key structural proteins, including the Spike glycoprotein, which mediates viral entry into host cells. Within Spike, the S2 subunit, and particularly its fusion domain, plays a critical role in merging viral and host membranes. To explore how receptor-driven Spike clustering influences this process, we investigated the self-assembly of S2 fusion peptides (FPs) and their interactions with biomimetic plasma membrane (PM) models composed of phospholipids, sphingomyelin, and cholesterol. Atomic force microscopy, laser direct infrared spectroscopy, neutron reflectometry, and grazing-incidence X-ray diffraction reveal that FPs form supramolecular assemblies that exclude cholesterol-rich nanodomains, increase membrane fluidity, and disrupt raft-like order associated with ACE2 binding. The appearance of spiral FP fibers supports a loaded-spring mechanism for membrane remodeling, offering a model for cooperative peptide-driven fusion, highlighting opportunities for antiviral and nanobiotechnological applications.