%0 Journal Article
%A Khaled, Mohammed
%A Strodel, Birgit
%A Sayyed-Ahmad, Abdallah
%T Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers
%J Frontiers in molecular biosciences
%V 10
%@ 2296-889X
%C Lausanne
%I Frontiers
%M FZJ-2023-01933
%P 1143353
%D 2023
%X Polyglutamine expansion at the N-terminus of the huntingtin protein exon 1 (Htt-ex1) is closely associated with a number of neurodegenerative diseases, which result from the aggregation of the increased polyQ repeat. However, the underlying structures and aggregation mechanism are still poorly understood. We performed microsecond-long all-atom molecular dynamics simulations to study the folding and dimerization of Htt-ex1 (about 100 residues) with non-pathogenic and pathogenic polyQ lengths, and uncovered substantial differences. The non-pathogenic monomer adopts a long α-helix that includes most of the polyQ residues, which forms the interaction interface for dimerization, and a PPII-turn-PPII motif in the proline-rich region. In the pathogenic monomer, the polyQ region is disordered, leading to compact structures with many intra-protein interactions and the formation of short β-sheets. Dimerization can proceed via different modes, where those involving the N-terminal headpiece bury more hydrophobic residues and are thus more stable. Moreover, in the pathogenic Htt-ex1 dimers the proline-rich region interacts with the polyQ region, which slows the formation of β-sheets.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 37101557
%U <Go to ISI:>//WOS:000976593100001
%R 10.3389/fmolb.2023.1143353
%U https://juser.fz-juelich.de/record/1006994