# Multiscale Simulations Elucidate the Mechanism of Polyglutamine Aggregation and the Role of Flanking Domains in Fibril Polymorphism

## TL;DR

This study uses simulations to understand how polyglutamine proteins form amyloid fibrils and how flanking domains influence this process in diseases like Huntington’s.

## Contribution

The study introduces new insights into polyQ aggregation mechanisms and the role of the N17 domain in controlling fibril polymorphism.

## Key findings

- PolyQ aggregation produces heterogeneous amyloid fibrils with variable-width branched morphologies.
- The N17 domain reduces fibril heterogeneity by favoring β-strand conformations.
- Early aggregation involves two mechanisms: backbone interactions and side-chain interdigitation.

## Abstract

Protein aggregation,
which is implicated in aging and neurodegenerative
diseases, typically involves a transition from soluble monomers and
oligomers to insoluble fibrils. Polyglutamine (polyQ) tracts in proteins
can form amyloid fibrils, which are linked to polyQ diseases, including
Huntington’s disease (HD), where the length of the polyQ tract
inversely correlates with the age of onset. Despite significant research
on the mechanisms of Httex1 aggregation, atomistic information regarding
the intermediate stages of its fibrillation and the morphological
characteristics of the end-state amyloid fibrils remains limited.
Recently, molecular dynamics (MD) simulations based on a hybrid multistate
structure-based model, Multi-eGO, have shown promise in capturing
the kinetics and mechanism of amyloid fibrillation with high computational
efficiency while achieving qualitative agreement with experiments.
Here, we utilize the Multi-eGO simulation methodology to study the
mechanism and kinetics of polyQ fibrillation and the effect of the
N17 flanking domain of the huntingtin protein. Aggregation simulations
of polyQ produced highly heterogeneous amyloid fibrils with variable-width
branched morphologies by incorporating combinations of β-turn,
β-arc, and β-strand structures, while the presence of
the N17 flanking domain reduced amyloid fibril heterogeneity by favoring
β-strand conformations. Our simulations reveal that the presence
of the N17 domain enhanced aggregation kinetics by promoting the formation
of large, structurally stable oligomers. Furthermore, the early-stage
aggregation process involves two distinct mechanisms: backbone interactions
driving β-sheet formation and side-chain interdigitation. Overall,
our study provides detailed insights into the fibrillation kinetics,
mechanisms, and end-state polymorphism associated with Httex1 amyloid
aggregation.