# Anion Binding and Aggregation of N‑Terminal α‑Synuclein Peptides

## TL;DR

This study explores how anions affect the structure and aggregation of α-synuclein peptides linked to Parkinson's disease.

## Contribution

The paper reveals that anion binding influences α-synuclein aggregation through charge screening and follows a reverse Hofmeister effect.

## Key findings

- Anions bind weakly to the midsection of N-terminal α-synuclein peptides without inducing long-range ordering.
- Anion binding reduces the effective positive charge, promoting aggregation via a reverse Hofmeister effect.
- Aggregation follows the Finke–Watzky model at intermediate salt concentrations or low pH.

## Abstract

α-Synuclein (α-Syn) is linked to the pathogenesis
of
Parkinson’s disease by its misfolding, aggregation, and accumulation
in Lewy bodies, the characteristic amyloids of Parkinson’s. N-terminal binding to phospholipid membranes and the resulting
random-coil to helical transition are key to the aggregation of α-Syn.
However, despite the recognized affinity for the N-terminal domain for phospholipids, the anion affinity for this region
has not been comprehensively examined. To probe the effects of monovalent
anion binding to the N-terminus, we report here on
studies with the 15-mer N-terminal peptide of α-Syn
and two mutants in which all three lysines of the wild-type sequence
are replaced with either arginine or histidine (1MDVFM
X
GLS
X
A
X
EGV15;
X
= K, R, or H). Our studies reveal that charge-diffuse
anions have a measurable affinity, binding weakly to the midsection
of the sequences. However, binding does not induce significant long-range
ordering. Nevertheless, MD simulations do reveal a compaction of the
peptides in the presence of ClO4
–, supporting
the conclusion that anion binding screens the positively charged residues,
reducing the effective net positive charge of the peptide and inducing
aggregation. Aggregation studies revealed that this reverse Hofmeister
effect correlates with anion affinity and that at intermediate salt
concentrations or low pH, aggregation follows the Finke–Watzky
model. Our findings suggest that changes in simple salt concentrations
are unlikely to affect the structure of the N-terminal
region of α-Syn and highlight that multipoint interactions between
polyanionic phospholipid membranes are a necessary requirement for
the random-coil to helical transition observed in the wild type.