Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers

Polyglutamine expansion at the N-terminus of the huntingtin protein exon 1 (Httex1) 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 nonpathogenic and pathogenic polyQ lengths, and uncovered substantial differences. The non-pathogenic monomer adopts a long a-helix that includes most of the polyQ residues, which forms the interaction interface for dimerization, and a PPIIturn-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 ss-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 Httex1 dimers the proline-rich region interacts with the polyQ region, which slows the formation of ss-sheets.

Automated summary

Polyglutamine expansion in the huntingtin protein exon 1 is associated with neurodegenerative diseases. Molecular dynamics simulations revealed differences between nonpathogenic and pathogenic forms of Htt-ex1. The nonpathogenic monomer adopts a long alpha-helix, while the pathogenic monomer has a disordered polyglutamine region and forms compact structures with beta-sheets.