Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic

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 m...

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Autores principales:	Adrien Guzzo, Patrice Delarue, Ana Rojas, Adrien Nicolaï, Gia G. Maisuradze, Patrick Senet
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	α-synuclein amyloid Parkinson disease molecular dynamics dictionary of secondary structure of proteins CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/112f16c14a3c47bbb2e9336e93c00391
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spelling	oai:doaj.org-article:112f16c14a3c47bbb2e9336e93c003912021-12-01T13:58:49ZMissense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic2296-889X10.3389/fmolb.2021.786123https://doaj.org/article/112f16c14a3c47bbb2e9336e93c003912021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.786123/fullhttps://doaj.org/toc/2296-889Xα-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, Rg, or probability distribution of Rg cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of Rg are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the α-synuclein monomer.Adrien GuzzoPatrice DelarueAna RojasAdrien NicolaïGia G. MaisuradzePatrick SenetPatrick SenetFrontiers Media S.A.articleα-synucleinamyloidParkinson diseasemolecular dynamicsdictionary of secondary structure of proteinsCUrvature and Torsion based of Alpha-helix and Beta-sheet IdentificationBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	α-synuclein amyloid Parkinson disease molecular dynamics dictionary of secondary structure of proteins CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification Biology (General) QH301-705.5
spellingShingle	α-synuclein amyloid Parkinson disease molecular dynamics dictionary of secondary structure of proteins CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification Biology (General) QH301-705.5 Adrien Guzzo Patrice Delarue Ana Rojas Adrien Nicolaï Gia G. Maisuradze Patrick Senet Patrick Senet Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
description	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, Rg, or probability distribution of Rg cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of Rg are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the α-synuclein monomer.
format	article
author	Adrien Guzzo Patrice Delarue Ana Rojas Adrien Nicolaï Gia G. Maisuradze Patrick Senet Patrick Senet
author_facet	Adrien Guzzo Patrice Delarue Ana Rojas Adrien Nicolaï Gia G. Maisuradze Patrick Senet Patrick Senet
author_sort	Adrien Guzzo
title	Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
title_short	Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
title_full	Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
title_fullStr	Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
title_full_unstemmed	Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic
title_sort	missense mutations modify the conformational ensemble of the α-synuclein monomer which exhibits a two-phase characteristic
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/112f16c14a3c47bbb2e9336e93c00391
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Missense Mutations Modify the Conformational Ensemble of the α-Synuclein Monomer Which Exhibits a Two-Phase Characteristic

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