%0 Journal Article
%T From a Highly Disordered to a Metastable State: Uncovering Insights of ¦Á-Synuclein
%J -
%D 2018
%R https://doi.org/10.1021/acschemneuro.7b00446
%X ¦Á-Synuclein (¦ÁS) is a major constituent of Lewy bodies, the insoluble aggregates that are the hallmark of one of the most prevalent neurodegenerative disorders, Parkinson¡¯s disease (PD). The vast majority of experiments in vitro and in vivo provide extensive evidence that a disordered monomeric form is the predominant state of ¦ÁS in water solution, and it undergoes a large-scale disorder-to-helix transition upon binding to vesicles of different types. Recently, another form, tetrameric, of ¦ÁS with a stable helical structure was identified experimentally. It has been shown that a dynamic intracellular population of metastable ¦ÁS tetramers and monomers coexists normally; and the tetramer plays an essential role in maintaining ¦ÁS homeostasis. Therefore, it is of interest to know whether the tetramer can serve as a means of preventing or delaying the start of PD. Before answering this very important question, it is, first, necessary to find out, on an atomistic level, a correlation between tetramers and monomers; what mediates tetramer formation and what makes a tetramer stable. We address these questions here by investigating both monomeric and tetrameric forms of ¦ÁS. In particular, by examining correlations between the motions of the side chains and the main chain, steric parameters along the amino-acid sequence, and one- and two-dimensional free-energy landscapes along the coarse-grained dihedral angles ¦Ã and ¦Ä and principal components, respectively, in monomeric and tetrameric ¦ÁS, we were able to shed light on a fundamental relationship between monomers and tetramers, and the key residues involved in mediating formation of a tetramer. Also, the reasons for the stability of tetrameric ¦ÁS and inability of monomeric ¦ÁS to fold are elucidated here
%U https://pubs.acs.org/doi/10.1021/acschemneuro.7b00446