# Protein Recognition of Linear and Cyclic Peptides of Homologous Sequences Implicated in the Aggregation of α‑Synuclein

## TL;DR

This study explores how certain peptides interact with α-synuclein, a protein linked to Parkinson's disease, to prevent harmful aggregation.

## Contribution

The study uses molecular dynamics to compare how linear and cyclic peptides interact with homologous sequences in α-synuclein.

## Key findings

- Both linear and cyclic peptides show specificity toward homologous sequences in α-synuclein.
- Some peptides stabilize α-helices in α-synuclein's NAC region in membrane-like conditions.
- Certain peptides may disrupt intramolecular interactions that protect against aggregation.

## Abstract

Various amino acid sequences have been suggested to play
key roles
in the aggregation of α-synuclein (α-syn), implicated
in Parkinson’s disease and other synucleinopathies. A drug
development strategy is, therefore, the design of molecules that bind
to these sequences in the monomer. The latter, either alone or coupled
with antiaggregation groups, could preclude homogeneous and/or heterogeneous
primary nucleation by either blocking protein–protein interactions
or stabilizing the monomer in its solution and/or membrane-bound conformations,
respectively. Here, using molecular dynamics simulations, we assessed
the specificity of in trans linear peptides (P1,
NACore, and NACterm) and their cyclic counterparts toward homologous
sequences in the N-terminal and NAC domains of α-syn, which
have been experimentally shown to play key roles in aggregation. The
results suggest that, despite some differences, both linear and cyclic
peptides display specificity toward their homologous sequences in
α-syn. Hence, these peptides have the potential to serve as
recognition elements coupled with amyloid aggregation modulators or
inhibitors. Additionally, most peptides stabilize the α-helices
in the NAC region of α-syn when in a membrane-bond-like conformation
and some induce more extended conformations when in a disordered form.
However, our results also show that some peptides might eliminate
intramolecular interactions with potential protective roles against
aggregation. The results are further compared with the monomer at
high temperatures, at which the protein adopts a more compact structure,
and exhibits increased intramolecular β-sheet content, associated
with an increase of the hydrophobic effect.