Hang Yu, Wei Han, Wen Ma, and Klaus Schulten.
Transient β-hairpin formation in α-synuclein monomer
revealed by coarse-grained molecular dynamics simulation.
Journal of Chemical Physics, 143:243142, 2015.
(PMC: PMC4684271)
YU2015
Parkinson's disease is a common neurodegenerative disorder that originates
from the intrinsically disordered peptide -synuclein aggregating into
fibrils.
It remains unclear how -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 150 s in aggregated time) using a hybrid-resolution model, PACE,
to characterize in atomic detail structural ensembles of wild type and mutant
monomeric -synuclein in aqueous solution. The simulations reproduce
structural properties of -synuclein characterized in experiments, such
as secondary structure content, long-range contacts, chemical shifts and
J(HH)-coupling constants. Most notably, the
simulations reveal that a short fragment encompassing region 38-53, adjacent
to the non-Amyloid- component region, exhibits a high probability of
forming a -hairpin; this fragment, when isolated from the remainder of
-synuclein, fluctuates frequently into its -hairpin conformation.
Two disease-prone mutations, namely A30P and A53T, significantly accelerate
the formation of a -hairpin in the stated fragment. We conclude that
the formation of a -hairpin in region 38-53 is a key event during
-synuclein aggregation. We predict further that the G47V mutation
impedes the formation of a turn in the -hairpin and slows down
-hairpin formation, thereby retarding -synuclein aggregation.
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