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Receptor-ligand interactions are essential for biological function and theirbinding strength is commonly explained in terms of static lock-and-key modelsbased on molecular complementarity. However, detailed information of the fullunbinding pathway is often lacking due, in part, to the static nature of atomicstructures and ensemble averaging inherent to bulk biophysics approaches. Herewe combine molecular dynamics and high-speed force spectroscopy on thestreptavidin-biotin complex to determine the binding strength and unbindingpathways over the widest dynamic range. Experiment and simulation showexcellent agreement at overlapping velocities and provided evidence of theunbinding mechanisms. During unbinding, biotin crosses multiple energy barriersand visits various intermediate states far from the binding pocket whilestreptavidin undergoes transient induced fits, all varying with loading rate.This multistate process slows down the transition to the unbound state andfavors rebinding, thus explaining the long lifetime of the complex. We providean atomistic, dynamic picture of the unbinding process, replacing a simpletwo-state picture with one that involves many routes to the lock andrate-dependent induced-fit motions for intermediates, which might be relevantfor other receptor-ligand bonds.

Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations