The Physical Driving Forces of Conformational Transition for TTR91-96 with Proline Mutations
Yuanming Cao1, Pengxuan Xia1, Yanyan Zhu1
1College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China.
Journal of Chemical Information and Modeling
|November 8, 2024
Summary
This study investigates Transthyretin (TTR) protein misfolding and aggregation, key to Transthyretin amyloidosis (ATTR). Molecular dynamics simulations reveal how TTR91-96 sequences transition to amyloid structures, offering insights for drug design.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Transthyretin amyloidosis (ATTR) is linked to pathological aggregation of Transthyretin (TTR) proteins.
- The TTR91-96 sequence is critical for TTR self-aggregation, but its misfolding mechanisms remain unclear.
Purpose of the Study:
- To investigate the misfolding and self-assembly mechanisms of TTR91-96 octamers using molecular dynamics simulations.
- To analyze the impact of E92P and V94P mutations on TTR91-96 aggregation dynamics.
Main Methods:
- Microsecond molecular dynamics simulations were employed to study TTR91-96 octamers and their mutants.
- Analysis focused on conformational transitions, hydrophobic interactions, and π-π stacking patterns.
Main Results:
- Hydrophobic interactions and π-π stacking were found to reduce β-sheet content in V94P and E92P mutants.
- The TTR91-96 octamer undergoes a conformational transition from closed β-barrel to open β-barrel and finally to β-bilayer aggregation.
- The dynamic mechanism of transition from intermediate to stable aggregated states was elucidated.
Conclusions:
- Understanding TTR91-96 aggregation dynamics provides crucial insights into Transthyretin amyloidosis pathogenesis.
- This research lays the groundwork for developing targeted therapeutic strategies against TTR amyloid diseases.
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