Abstract
α-Synuclein is an intrinsically disordered protein occurring in different conformations and prone to aggregate in β-sheet structures, which are the hallmark of the Parkinson disease. Missense mutations are associated with familial forms of this neuropathy. How these single amino-acid substitutions modify the conformations of wild-type α-synuclein is unclear. Here, using coarse-grained molecular dynamics simulations, we sampled the conformational space of the wild type and mutants (A30P, A53P, and E46K) of α-synuclein monomers for an effective time scale of 29.7 ms. To characterize the structures, we developed an algorithm, CUTABI (CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification), to identify residues in the α-helix and β-sheet from Cα -coordinates. CUTABI was built from the results of the analysis of 14,652 selected protein structures using the Dictionary of Secondary Structure of Proteins (DSSP) algorithm. DSSP results are reproduced with 93% of success for 10 times lower computational cost. A two-dimensional probability density map of α-synuclein as a function of the number of residues in the α-helix and β-sheet is computed for wild-type and mutated proteins from molecular dynamics trajectories. The density of conformational states reveals a two-phase characteristic with a homogeneous phase (state B, β-sheets) and a heterogeneous phase (state HB, mixture of α-helices and β-sheets). The B state represents 40% of the conformations for the wild-type, A30P, and E46K and only 25% for A53T. The density of conformational states of the B state for A53T and A30P mutants differs from the wild-type one. In addition, the mutant A53T has a larger propensity to form helices than the others. These findings indicate that the equilibrium between the different conformations of the α-synuclein monomer is modified by the missense mutations in a subtle way. The α-helix and β-sheet contents are promising order parameters for intrinsically disordered proteins, whereas other structural properties such as average gyration radius, R g , or probability distribution of R g cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of R g are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the α-synuclein monomer.
Highlights
Reviewed by: Leonid Breydo, West Pharmaceutical Services, United States Fabio Sterpone, UPR9080 Laboratoire de Biochimie Théorique (LBT), France
To avoid the high computational cost of all-atom reconstructions from coarse-grained coordinates, we developed here an algorithm which assigns an α-helix or a β-sheet secondary structure to each residue based on the Cα-Cα distances and on the coarse-grained angles formed by Cα-Cα pseudobonds, which correspond to the local curvature and torsion of the protein main chain (Grassein et al, 2020)
The present analysis is based on a first-principle very large conformational sampling of the WT α-syn and mutants
Summary
Reviewed by: Leonid Breydo, West Pharmaceutical Services, United States Fabio Sterpone, UPR9080 Laboratoire de Biochimie Théorique (LBT), France. The formation of long β-sheets differs significantly from α-helices as the former necessarily involves long-distance contacts in the sequence and depends on the mean curvature of the fold (Koh et al, 2006; Bhattacharjee and Biswas, 2010) The content of these two secondary structure elements is a criterion for classification of protein native structures and characterization of protein folding kinetics and pathways (Konagurthu et al, 2020). Α-syn is a 140 amino-acid protein abundant in the brain (Jakes et al, 1994; Mollenhauer et al, 2008) It plays a central role in the onset of the Parkinson disease (PD) and other neurological disorders, named synucleopathies (Soto, 2003; Chiti and Dobson, 2006; Stefanis, 2012; Chiti and Dobson, 2017; Tanudjojo et al, 2021). The different polymorphs characterized in vitro are believed to mimic the α-syn filament structures in synucleopathies
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