Force-Activated Slip-Catch-Slip Bonds Stabilize Virus Interactions

Viral adhesion often relies on dynamic molecular interactions that adapt to mechanical stress. Here, we report that SARS-CoV-2 spike proteins form catch bonds with the human ACE2 receptor, whereby moderate tensile forces enhance bond lifetimes before yielding at higher loads. Using single-molecule atomic force spectroscopy, we quantitatively resolved these nonmonotonic force–lifetime relationships for Alpha, Delta, and Omicron variants. The catch-bond regime between 15–35 pN reveals a mechanically tuned adhesion mechanism that may stabilize viral attachment in the dynamic respiratory environment. A two-state-two-pathway kinetic model reproduces the observed slip–catch–slip behavior, demonstrating that mechanical force can transiently strengthen viral receptor binding. These findings uncover a previously unrecognized biophysical strategy of SARS-CoV-2 that may influence infectivity and transmission.