All-atom simulations reveal how single point mutations promote serpin misfolding

Fang Wang; Simone Orioli; Alan Ianeselli; Giovanni Spagnolli; Silvio a Beccara; Anne Gershenson; Pietro Faccioli; Patrick L. Wintrode

doi:10.1016/j.bpj.2018.03.027

arXiv · 1707.05019

All-atom simulations reveal how single point mutations promote serpin misfolding

Fang Wang·Simone Orioli·Alan Ianeselli·Giovanni Spagnolli·Silvio a Beccara·Anne Gershenson·Pietro Faccioli·Patrick L. Wintrode

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Abstract

Protein misfolding is implicated in many diseases, including the serpinopathies. For the canonical inhibitory serpin α1-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.

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Fang Wang, Simone Orioli, Alan Ianeselli, Giovanni Spagnolli, Silvio a Beccara, Anne Gershenson, Pietro Faccioli, Patrick L. Wintrode. 2018-06-18. All-atom simulations reveal how single point mutations promote serpin misfolding. https://doi.org/10.1016/j.bpj.2018.03.027

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