6533b828fe1ef96bd12894c2

RESEARCH PRODUCT

Effects of mutations of wild-type alpha-synuclein on its structure and dimerization and consequences for the Parkinson's disease : answers from coarse-grained molecular dynamics simulations

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description

Alpha-synuclein is a protein of 140 amino acids, intrinsically disordered and found abundantly in the brain and whose toxic aggregation there is the hallmark of the Parkinson's disease.The aim of the thesis is to understand the effects of certain mutations on the dimerization of alpha-synuclein and to contribute to understand its involvement in Parkinson's disease by using coarse-grained molecular dynamics. Coarse-grained molecular dynamics trajectories were computed using the UNited-RESidue (UNRES) program and provided unprecedented sampling (over an effective time of the order of milliseconds) of the alpha-synuclein structures in monomeric and dimeric forms. These data were generated both for the wild-type protein but also for different types of mutants, related to the onset of an early form of the disease, or artificial and synthesized in order to understand the role of certain amino acids on the protein structure and aggregation. The study of this very large set of structures led us to build a program CUTABI, CUrvature and Torsion based Alpha helix and Beta sheet Identification) to detect secondary structures from coarse-grain models with a computational time of an order of magnitude smaller than the standard programs.From our molecular dynamics simulations, we identified two phases in the conformational set of monomers: a first phase composed of conformations without helices and a second phase composed of conformations with both helices and β-sheets. We also identified a particular region of the sequence forming a characteristic β-sheet hairpin. We demonstrated that this type of secondary structure element is much more present in the wild-type protein compared to all the toxic mutants studied.Study of the dimer conformations allowed us to identify two main regions of aggregation along the amino-acid sequence of alpha-synuclein and to demonstrate the existence of two main types of dimeric structures. The first type (minority of the conformations), named pre-fibrillar in this thesis, consists of structures with contacts between residues at the same positions along the amino-acid sequence in the monomers forming the dimer, similar to the contacts between the residues of the monomers of the fibrillar structures observed in vitro. This type of contacts only forms in a single region of the sequence for the wild-type protein against several regions of the sequence for certain mutants. Moreover, these fibrillar-type dimers are more abundant in toxic mutants. The second type (majority of the conformations), is made up of disordered structures with variable numbers of intra-molecular and inter-molecular contacts. In this last type of structures, we identified a subfamily of very aggregated dimers forming very long parallel β-sheets, also more abundant for the mutants studied than for the wild-type protein.All results obtained are discussed and compared with all the structural and mutagenesis experimental data available.