Serine protease inhibitors (serpins) are the largest family of protease inhibitors. They have evolved to inhibit a specific serine protease in many important biological functions. The serpin’s specificity is believed to reside in the reactive center loop, a protruding loop where the target serine protease binds and cleaves. Previously, we have created a synthetic, active serpin-conserpin- that is significantly more stable and less prove to misfolding and aggregation than a typical serpin (Porebski et al. 2016). Here, we used conserpin to explore what structural and dynamic requirements are necessary for a serpin’s specificity to a target protease. Conserpin’s reactive center loop was mutated to match that of alpha1-antitrypsin (a1-AT). This new conserpin retained its thermostability, but did not contain a1-AT specificity. Determination of its X-ray crystallography structure, followed by molecular dynamics studies, suggest that a serpin’s specificity is dependent on the relationship between its structure and dynamics in regions not only within the reactive center loop, but regions of serpin’s body that this loop interacts with.