Understanding how heparin modulates membrane interactions relevant to SARS-CoV-2 entry is essential for elucidating its antiviral mechanisms. Here, Langmuir monolayers were used as biomimetic models of viral and host membranes to investigate interactions with the spike receptor-binding domain (RBD), ACE2, and heparin. Surface pressure–area isotherms, dilatational rheology, Brewster angle microscopy, and PM-IRRAS revealed lipid-dependent effects. In viral-model monolayers, RBD and heparin significantly disrupted film organization, decreasing elasticity and increasing dissipative behavior, with the RBD–heparin complex producing the most pronounced fluidization despite increased local chain order. In host-model monolayers, ACE2 was the main perturbing agent, while heparin primarily interacted with ACE2 without major additional disruption; subsequent RBD addition induced moderate structural reorganization. Notably, opposing trends between compressional and dynamic moduli highlight distinct relaxation regimes governing interfacial mechanics. Overall, heparin acts as a membrane-active modulator, altering interfacial organization and mechanics in a lipid-dependent manner. These findings suggest that, beyond direct protein binding, heparin may interfere with SARS-CoV-2 infection through membrane-mediated mechanisms. • Heparin modulates lipid monolayers in a lipid-dependent manner. • RBD–heparin complexes strongly disrupt DPPS membrane organization. • ACE2 is the main perturbing agent in cholesterol monolayers. • Local chain ordering increases while global elasticity decreases. • Membrane effects complement heparin's known protein-binding activity.
Pantarotto et al. (Fri,) studied this question.