Force-regulated catch bonds and fusion peptide exposure drive coronavirus entry

Abstract

Coronaviruses invade human cells within dynamic mechanical environments through endocytosis and membrane fusion, both mediated by the class I fusion protein spike. In SARS-CoV and SARS-CoV-2, the spike engages the human ACE2 receptor through a catch bond--an interaction whose lifetime increases under tensile force. Concurrently, mechanical pulling facilitates disruption of the S1/S2 subunits of spike, a critical step for membrane fusion. To elucidate how mechanical cues coordinate these processes, we developed a unified elastic-stochastic model that integrates theoretical analysis and computational simulations to trace viral entry. Our results identify the force-regulated catch bond between spike and ACE2 as a key determinant of successful invasion. This catch bond not only enhances receptor-mediated endocytosis but also increases the probability of S1/S2 disengagement, thereby promoting membrane fusion. Importantly, under conditions of strong catch bonding, the force-accelerated separation of S1 and S2 fine-tunes the balance between entry pathways. These findings uncover a potential mechanobiological mechanism that mediates viral cell entry by coupling receptor binding strength with spike disassembly under force. By characterizing these mechanical regulations, this work facilitates the assessment of emerging viral threats and inspires the design of drug delivery systems that leverage catch-bond kinetics for enhanced targeting.