1. All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding
- Author
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S. a Beccara, Pietro Faccioli, Giovanni Spagnolli, Fang Wang, Simone Orioli, Anne Gershenson, Patrick L. Wintrode, Alan Ianeselli, Wang, F, Orioli, S, Ianeselli, A, Spagnolli, G, a Beccara, S, Gershenson, A, Faccioli, P, and Wintrode, P
- Subjects
0301 basic medicine ,Protein Folding ,Protein Conformation ,Mutant ,Biophysics ,FOS: Physical sciences ,Condensed Matter - Soft Condensed Matter ,Serpin ,Molecular Dynamics Simulation ,medicine.disease_cause ,01 natural sciences ,law.invention ,03 medical and health sciences ,Protein structure ,Mutant Protein ,law ,0103 physical sciences ,medicine ,Point Mutation ,Physics - Biological Physics ,Genetics ,Mutation ,010304 chemical physics ,Chemistry ,Point mutation ,Proteins ,Biomolecules (q-bio.BM) ,Folding (chemistry) ,030104 developmental biology ,Quantitative Biology - Biomolecules ,Biological Physics (physics.bio-ph) ,FOS: Biological sciences ,alpha 1-Antitrypsin ,Suppressor ,Soft Condensed Matter (cond-mat.soft) ,Mutant Proteins ,Protein folding - Abstract
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., Comment: Final version. Supplementary Information included
- Published
- 2018