Exploration of the Misfolding Mechanism of Transthyretin Monomer: Insights from Hybrid-Resolution Simulations and Markov State Model Analysis.

ABSTRACT: Misfolding and aggregation of transthyretin (TTR) is widely known to be responsible for a progressive systemic disorder called amyloid transthyretin (ATTR) amyloidosis. Studies suggest that TTR aggregation is initiated by a rate-limiting dissociation of the homo-tetramer into its monomers, which can rapidly misfold and self-assemble into amyloid fibril. Thus, exploring conformational change involved in TTR monomer misfolding is of vital importance for understanding the pathogenesis of ATTR amyloidosis. In this work, microsecond timescale hybrid-resolution molecular dynamics (MD) simulations combined with Markov state model (MSM) analysis were performed to investigate the misfolding mechanism of the TTR monomer. The results indicate that a macrostate with partially unfolded conformations ma

SUBMITTER: Zhou S 

PROVIDER: S-EPMC6995605 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature