Alpha-1 antitrypsin (α1-AT) is a serine protease inhibitor (serpin) that plays an important role in the protection of the lungs from endogenous proteases. Several disease-causing mutations have been found to result in polymerization of α1-AT, forming inactive aggregates in the liver. The resulting α1-AT deficiency is linked to various diseases, such as cirrhosis, emphysema, and hepatocellular carcinoma. It is suggested that polymerization of α1-AT is a result of insertion of the RCL of a second molecule into β-sheet A. It has yet remained unclear whether this insertion occurs during folding, or from the folded form. Kass et al. have previously shown that the Z-variant (E342K) – the most common disease-causing mutation – affects the dynamics of the top of β-sheet A, resulting in a more open state. This renders the molecule more prone to polymerization. In order to investigate the polymerization mechanism of other α1-AT mutants, we have performed comparative simulations of the following in silico mutations of α1-AT: F52x (Mmalton), S53F (Siiyama), K154N (Queen’s), K259I (Mpisa), K368E (Etaurisano), and P391H (Yorzinuovi/Ybarcelona). Our results indicate that some mutations do not affect the dynamics of the protein in its native state, suggesting that polymerization occurs during folding.