All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding

Biophys J. 2018 May 8;114(9):2083-2094. doi: 10.1016/j.bpj.2018.03.027.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Molecular Dynamics Simulation*
  • Mutant Proteins / chemistry*
  • Mutant Proteins / genetics
  • Point Mutation*
  • Protein Conformation
  • Protein Folding*
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / genetics

Substances

  • Mutant Proteins
  • alpha 1-Antitrypsin