  Protein misfolding is implicated in many diseases, including the
serpinopathies. For the canonical inhibitory serpin {\alpha}1-antitrypsin
(A1AT), mutations can result in protein deficiencies leading to lung disease,
and misfolded mutants can accumulate in hepatocytes leading to liver disease.
Using all-atom simulations based on the recently developed Bias Functional
algorithm we elucidate how wild-type A1AT folds and how the disease-associated
S (Glu264Val) and Z (Glu342Lys) mutations lead to misfolding. The deleterious Z
mutation disrupts folding at an early stage, while the relatively benign S
mutant shows late stage minor misfolding. A number of suppressor mutations
ameliorate the effects of the Z mutation and simulations on these mutants help
to elucidate the relative roles of steric clashes and electrostatic
interactions in Z misfolding. These results demonstrate a striking correlation
between atomistic events and disease severity and shine light on the mechanisms
driving chains away from their correct folding routes.
