The study by Grubmüller, Heymann, and Tavan investigates the force required to rupture the streptavidin-biotin complex using computer simulations. The computed force aligns well with experimental data from atomic force microscopy (AFM) experiments. The simulations reveal a detailed multiple-pathway rupture mechanism involving five major unbinding steps. The binding force is attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, water bridges significantly enhance the complex's stability, while steric restraints do not contribute to the binding forces. The simulations also show that conformational motions occur but do not significantly affect the binding interactions. The findings provide insights into the molecular basis of ligand-receptor interactions and the specificity of these interactions.The study by Grubmüller, Heymann, and Tavan investigates the force required to rupture the streptavidin-biotin complex using computer simulations. The computed force aligns well with experimental data from atomic force microscopy (AFM) experiments. The simulations reveal a detailed multiple-pathway rupture mechanism involving five major unbinding steps. The binding force is attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, water bridges significantly enhance the complex's stability, while steric restraints do not contribute to the binding forces. The simulations also show that conformational motions occur but do not significantly affect the binding interactions. The findings provide insights into the molecular basis of ligand-receptor interactions and the specificity of these interactions.