The field of computational structural biology has been spearheaded by the successful use of molecular dynamics simulations to study the dynamics of proteins and their relationship to their function. Molecular dynamics simulations together with improved free energy calculations have enabled computational chemists to play a key role in the field of rational drug design. Molecular dynamics simulations are limited, however, to the protein motions that occur on the nano- to microsecond timescales. For large conformational changes, for example those associated with protein activation or inactivation, enhanced sampling is needed to fully understand the mechanism of the process involved. Accelerated molecular dynamics (aMD) is one example of these methods that is being developed and improved in the McCammon group. This approach has been shown to produce results which are in quantitative agreement with experimental data such as NMR observables. Our lab studies the activation of serine proteases. We will focus our attention to thrombin, which plays a pivotal role in the clotting cascade cleaving fibrinogen as part of the clotting process and activating protein C, thus initiating anticoagulation. Improved inhibitors of thrombin are common therapeutics for thrombogenesis and clotting events. Localized in the blood, this protein is mainly present in its inactive zymogen form called prothrombin and maintains normal hemostasis. Upon cleavage prothrombin becomes the active form. An understanding of the key changes in dynamics during the activation of thrombin from protothrombin will greatly aid in the design of future direct thrombin inhibitors. By shifting from a molecular model to studying large protein-protein interactions, we will be able to understand at the molecular level events involved in thrombogenesis. Using such a multi-scale approach, we can both apply a new molecular understanding of a critical part of the clotting cascade to the design of direct thrombin inhibitors as well as extend these questions to other serine proteases.