Ioana Mariuca Ilie: Amyloid fibril growth: a multiscale view

The accumulation of amyloid fibrils is the hallmark of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease [1]. The proteins associated with these disorders are α-synuclein and the amyloid-β peptide, respectively.

Here we use coarse-grain and atomistic simulations to explore the intricate dynamics and aggregation of alpha-synuclein [2,3], and the structural rearrangements of amyloid-β(42) monomers during fibril elongation [4].

We introduce a novel coarse-grain model to represent α-synuclein as a chain of deformable particles that can adapt their geometry, binding affinities and can rearrange into different disordered and ordered structures [3]. Combined with atomistic simulations, results offer valuable insight into the internal dynamics of α-synuclein [2] and indicate that a protein attaching to a mature fibril easily gets trapped in a sub-optimal configuration, explaining the experimentally observed stop-and-go growth of an amyloid fibril [3].

Next, we use atomistic simulations to explore the fibril stability and early events of peptide dissociation from a fibril of the Alzheimer’s amyloid-β(42) peptide [4]. Simulations show structural stability of the fibrillar core and a high flexibility registered at the tip peptides. In particular, residues 21-29 dissociate in most simulations, while residues 15-20 and 35-41 remain closely attached to the fibril. The N-termini of all peptides are flexible and adopt mainly disordered conformations with transient structuring. The tip peptides can associate with the adjacent layers occasionally in an ordered fashion. From an extended analysis of the N-termini, we hypothesize that they most likely also contribute to the stop-and-go mechanism of amyloid growth by shielding the fibrillar template and hindering growth by monomer addition to the fibrillary end.

References:

[1] I.M. Ilie & A. Caflisch, Chem. Rev. 119: 6956–6993 (2019)

[2] I.M. Ilie et al., J. Chem. Theory Comput., 14:3298–3310 (2018)

[3] I.M. Ilie et al., J. Chem. Phys., 146:115102 (2017)

[4] I.M. Ilie & A. Caflisch, J. Phys. Chem. B, 122:11072–11082 (2018)