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Accelerated Amyloid Aggregation Dynamics of Intrinsically Disordered Proteins in Heavy Water
Myung Kook Son1,2, Dongjoon Im3, Da Gyeong Hyun1,2
1Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
The Journal of Physical Chemistry Letters
|November 19, 2024
Summary
Deuterium oxide (D2O) accelerates amyloid intrinsically disordered protein (IDP) fibrillation by stabilizing beta-sheet structures and enhancing hydrophobic interactions, unlike in heavy water (H2O). This impacts protein analysis and understanding of amyloid diseases.
Area of Science:
- Biochemistry
- Structural Biology
- Protein Dynamics
Background:
- Amyloid intrinsically disordered proteins (IDPs) are implicated in various neurodegenerative diseases.
- Understanding the factors influencing IDP fibrillation kinetics and structural changes is crucial for disease mechanism studies.
- The role of heavy water (deuterium oxide, D2O) versus regular water (H2O) in protein dynamics is not fully elucidated.
Purpose of the Study:
- To investigate the influence of D2O on the fibrillation kinetics and structural dynamics of key amyloid IDPs.
- To compare the effects of D2O on IDPs versus structured proteins like insulin.
- To elucidate the molecular mechanisms behind D2O-mediated changes in protein fibrillation.
Main Methods:
- Fibrillation kinetics assays were performed for IDPs (α-synuclein, amyloid-β 1-42, K18) in H2O and D2O.
- Structural characterization utilized electrospray ionization ion mobility mass spectrometry (ESI-IM-MS) and small-angle X-ray scattering (SAXS).
- Molecular dynamics (MD) simulations and umbrella sampling were employed to analyze protein-solvent interactions and fibril stability.
Main Results:
- IDP fibrillation was significantly accelerated in D2O compared to H2O, contrasting with the behavior of structured insulin.
- Structural investigations revealed no significant changes in IDP structures that could account for the accelerated fibrillation in D2O.
- D2O enhanced hydrogen bonding and hydrophobic interactions, leading to stabilized β-sheet structured fibrils.
Conclusions:
- D2O promotes faster fibrillation of amyloid IDPs by stabilizing the critical β-sheet structures and creating a more hydrophobic environment.
- The findings underscore the importance of considering the solvent's isotopic composition (H2O vs. D2O) in protein structural and kinetic studies.
- This research provides critical insights into the differential effects of D2O on protein interactions, relevant for amyloidosis research and biophysical analyses.
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