Interaction of glycoprotein Iba(GPIba) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. Arterial blood flow enhances binding of GPIba to VWF. Mutations in the VWF A1 domain that cause type 2B von Willebrand disease (VWD) reduce the flow requirement for adhesion. Single molecule experiments show that increasing force on GPIba/VWF bonds first prolonged (catch) and then shortened (slip) lifetimes. Two type 2B VWD A1 mutants, R1306Q and R1450E, eliminated catch bonds by prolonging lifetimes at low forces. Steered molecular dynamics simulations of GPIba dissociating from A1 suggested mechanisms for catch bonds that A1 mutations eliminated. A major contact between GPIba and VWF involves the β-switch region, which is a loop in the unliganded GPIba but switches to a β-hairpin in the complex structure. Mutations in the GPIba β-hairpin may cause platelet-type VWD. The gain-of-function mutations (e.g., M239V) reduce the flow requirement for VWF binding, whereas loss-of-function mutations (e.g., A238V) increase the flow requirement. We demonstrate that the β-hairpin is unstable without contacting VWF, in that it switches to a loop in free molecular dynamics simulations. Simulations with a novel flow molecular dynamics algorithm show that the loop conformation is unstable in the presence of flow, as it switches to β-hairpin even
without contacting VWF. Compared with the wild-type, it is easier for the M239V mutant but harder for the A238V mutant to switch to β-hairpin in the presence of flow. These results elucidate the structural basis for the two mutants and suggest a regulatory mechanism by which flow activates GPIba via inducing a loop-to-β-hairpin conformational transition on the β-switch, thereby promoting VWF binding.