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Title: Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation

Abstract

Parkinson’s disease, originating from the intrinsically disordered peptide α-synuclein, is a common neurodegenerative disorder that affects more than 5% of the population above age 85. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 180 μs in aggregated time) using a hybrid-resolution model, Proteins with Atomic details in Coarse-grained Environment (PACE), to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts, and {sup 3}J(H{sub N}H{sub C{sub α}})-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely, A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedesmore » the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.« less

Authors:
;  [1];  [1];  [1]
  1. Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 (United States)
Publication Date:
OSTI Identifier:
22493381
Resource Type:
Journal Article
Journal Name:
Journal of Chemical Physics
Additional Journal Information:
Journal Volume: 143; Journal Issue: 24; Other Information: (c) 2015 AIP Publishing LLC; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0021-9606
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; AGGLOMERATION; AQUEOUS SOLUTIONS; CHEMICAL SHIFT; CONFORMATIONAL CHANGES; COUPLING CONSTANTS; DISEASES; MOLECULAR DYNAMICS METHOD; MONOMERS; MUTANTS; MUTATIONS; PEPTIDES; RESOLUTION; TRANSIENTS

Citation Formats

Yu, Hang, Ma, Wen, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Han, Wei, Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Schulten, Klaus, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801. Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation. United States: N. p., 2015. Web. doi:10.1063/1.4936910.
Yu, Hang, Ma, Wen, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Han, Wei, Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Schulten, Klaus, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, & Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801. Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation. United States. https://doi.org/10.1063/1.4936910
Yu, Hang, Ma, Wen, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Han, Wei, Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Schulten, Klaus, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801. 2015. "Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation". United States. https://doi.org/10.1063/1.4936910.
@article{osti_22493381,
title = {Transient β-hairpin formation in α-synuclein monomer revealed by coarse-grained molecular dynamics simulation},
author = {Yu, Hang and Ma, Wen and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 and Han, Wei and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 and Schulten, Klaus and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801},
abstractNote = {Parkinson’s disease, originating from the intrinsically disordered peptide α-synuclein, is a common neurodegenerative disorder that affects more than 5% of the population above age 85. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 180 μs in aggregated time) using a hybrid-resolution model, Proteins with Atomic details in Coarse-grained Environment (PACE), to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts, and {sup 3}J(H{sub N}H{sub C{sub α}})-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely, A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.},
doi = {10.1063/1.4936910},
url = {https://www.osti.gov/biblio/22493381}, journal = {Journal of Chemical Physics},
issn = {0021-9606},
number = 24,
volume = 143,
place = {United States},
year = {Mon Dec 28 00:00:00 EST 2015},
month = {Mon Dec 28 00:00:00 EST 2015}
}