Abstract
The dimeric structure of the N-terminal 12 residues drives the interaction of α-synuclein protein with membranes. Moreover, experimental studies indicated that the aggregation of α-synuclein is faster at low pH than neutral pH. Nevertheless, the effects of different pH on the structural characteristics of the α-syn12 dimer remain poorly understood. We performed 500 ns temperature replica exchange molecular dynamics (T-REMD) simulations of two α-syn12 peptides in explicit solvent. The free energy surfaces contain ten highly populated regions at physiological pH, while there are only three highly populated regions contained at acidic pH. The anti-parallel β-sheet conformations were found as the lowest free energy state. Additionally, these states are nearly flat with a very small barrier which indicates that these states can easily transit between themselves. The dimer undergoes a disorder to order transition from physiological pH to acidic pH and the α-syn12 dimer at acidic pH involves a faster dimerization process. Further, the Lys6–Asp2 contact may prevent the dimerization.
Highlights
In Parkinson’s disease, the main component of the amyloid deposits found in Lewy bodies has been identified as α-synuclein protein, an intrinsically disorder protein with 140 residue acids [1,2].The aggregation of α-synuclein protein [3,4,5] and membrane binding [6] are two critical factors which led to Parkinson’s disease
The dimerization of α-synuclein is a key step in the aggregation progress [7], and the dimeric structures of α-synuclein bind preferentially with the lipid membrane in comparison to the monomeric protein [8]
The initial structure of the α-syn12 monomer with a sequence of MDVFMKGLSKAK(residues 1–12 of the human α-synuclein protein)was selected from the NMR-determined micelle bound structure at neutral pH (PDB ID: 1XQ8)
Summary
In Parkinson’s disease, the main component of the amyloid deposits found in Lewy bodies has been identified as α-synuclein protein, an intrinsically disorder protein with 140 residue acids [1,2]. The aggregation of α-synuclein protein [3,4,5] and membrane binding [6] are two critical factors which led to Parkinson’s disease. The dimerization of α-synuclein is a key step in the aggregation progress [7], and the dimeric structures of α-synuclein bind preferentially with the lipid membrane in comparison to the monomeric protein [8]. Exploration of the dimeric structures of α-synuclein are of significant interest. The N-terminal region (residues 1–60) of the α-synuclein protein, is involved in the dimerization and plays a key role in the formation of α-synuclein assemblies [9].
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