The Possible Structural Models for Polyglutamine Aggregation: A Molecular Dynamics Simulations Study

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial beta-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung beta-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high beta-turn and beta-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable beta-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of beta-turn and beta-sheet are sampled and preserved during the very early stage of aggregation.