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

TL;DR

This study uses all-atom simulations to reveal how specific mutations in the serpin protein alpha-1 antitrypsin cause misfolding, contributing to disease, and identifies molecular mechanisms underlying these effects.

Contribution

It introduces the application of Bias Functional all-atom simulations to elucidate mutation-induced misfolding mechanisms in serpins, highlighting early and late stage effects.

Findings

Z mutation disrupts early folding stages

S mutation causes minor late-stage misfolding

Suppressor mutations can mitigate Z mutation effects

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.