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Open AccessArticle

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

1
Chongqing Key Laboratory on Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
2
Department of Chemistry and Physical Sciences, Nicholls State University, P.O. Box 2022, Thibodaux, LA 70310, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(12), 889; https://doi.org/10.3390/biom9120889
Received: 29 November 2019 / Revised: 13 December 2019 / Accepted: 15 December 2019 / Published: 17 December 2019
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 may serve as the misfolded state of the TTR monomer. This misfolded state was extremely stable with a very large equilibrium probability of about 85.28%. With secondary structure analysis, we found the DAGH sheet in this state to be significantly destroyed. The CBEF sheet was relatively stable and sheet structure was maintained. However, the F-strand in this sheet was likely to move away from E-strand and reform a new β-sheet with the H-strand. This observation is consistent with experimental finding that F and H strands in the outer edge drive the misfolding of TTR. Finally, transition pathways from a near native state to this misfolded macrostate showed that the conformational transition can occur either through a native-like β-sheet intermediates or through partially unfolded intermediates, while the later appears to be the main pathway. As a whole, we identified a potential misfolded state of the TTR monomer and elucidated the misfolding pathway for its conformational transition. This work can provide a valuable theoretical basis for understanding of TTR aggregation and the pathogenesis of ATTR amyloidosis at the atomic level. View Full-Text
Keywords: protein misfolding; transthyretin amyloidosis; molecular dynamics simulation; Markov state model protein misfolding; transthyretin amyloidosis; molecular dynamics simulation; Markov state model
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Zhou, S.; Cheng, J.; Yang, T.; Ma, M.; Zhang, W.; Yuan, S.; Lo, G.V.; Dou, Y. Exploration of the Misfolding Mechanism of Transthyretin Monomer: Insights from Hybrid-Resolution Simulations and Markov State Model Analysis. Biomolecules 2019, 9, 889.

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