Fiche publication
Date publication
novembre 2021
Journal
Frontiers in molecular biosciences
Auteurs
Membres identifiés du Cancéropôle Est :
Dr NICOLAI Adrien
,
Dr DELARUE Patrice
,
Pr SENET Patrick
Tous les auteurs :
Guzzo A, Delarue P, Rojas A, Nicolaï A, Maisuradze GG, Senet P
Lien Pubmed
Résumé
-Synuclein is an intrinsically disordered protein occurring in different conformations and prone to aggregate in -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 -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 -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 -helix and -sheet from -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 -synuclein as a function of the number of residues in the -helix and -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, -sheets) and a heterogeneous phase (state HB, mixture of -helices and -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 -synuclein monomer is modified by the missense mutations in a subtle way. The -helix and -sheet contents are promising order parameters for intrinsically disordered proteins, whereas other structural properties such as average gyration radius, , or probability distribution of cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the -synuclein monomer.
Mots clés
CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification, PSEA, Parkinson disease, amyloid, dictionary of secondary structure of proteins, molecular dynamics, α-synuclein
Référence
Front Mol Biosci. 2021 11 29;8:786123
