Interaction of glycoprotein Ib alpha (GPIb alpha) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIb alpha and VWF involves the beta-switch region, which is a loop in the unliganded GPIb alpha but switches to a beta-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIb alpha-VWF binding. Gain-of-function mutations (e.g., M239V) in the beta-switch reduce the flow requirement for VWF binding, whereas loss-of-function mutations (e.g., A238V) increase the flow requirement. These phenomena cannot be explained by crystal structures or energy calculations. Herein we demonstrate that the beta-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 beta-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 beta-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 GPIb alpha via inducing a loop-to-beta-hairpin conformational transition on the beta-switch, thereby promoting VWF binding.