Work

Molecular Interplay of Small Molecules and Calcium Ions with α-Synuclein Revealed by NMR and Molecular Dynamics Simulations

Year: 2026

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Human α-synuclein is an intrinsically disordered protein concentrated at presynaptic terminals and strongly linked to Parkinson’s disease and other synucleinopathies. Its dynamic C-terminal region mediates interactions with small molecules and metal ions. Here, we used high-resolution nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations to characterize interactions between the C-terminal α-synuclein construct, the small molecule fasudil, and calcium ions. NMR data show that fasudil and Ca 2+ bind preferentially to overlapping regions enriched in alternating tyrosine and acidic residues while preserving the protein’s disordered nature. Side-chain-resolved spectra indicate distinct driving forces for fasudil and calcium binding. MD simulations reveal that Ca 2+ modifies the local electrostatic environment, decreasing fasudil interaction frequency through electrostatic screening and steric effects. Despite this, fasudil retains dynamic, reversible contacts with key tyrosine residues. Overall, exposed α-synuclein conformations allow simultaneous, ligand-specific interactions, highlighting side-chain hotspots governing binding in Ca 2+ -rich conditions.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.6c00106

Authors: Filippo Turchi, Haydar Taylan Turan, Marco Schiavina, Giuseppe Brancato, Isabella C. Felli, Roberta Pierattelli

Institutions: University of Florence, Scuola Normale Superiore

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500