Binding Sites for Luminescent Amyloid Biomarkers from non-Biased Molecular Dynamics Simulations

TL;DR

This study identifies a stable binding site for a luminescent amyloid biomarker using non-biased molecular dynamics simulations, revealing how binding affects probe conformation and luminescence properties relevant for Alzheimer's diagnostics.

Contribution

The paper uncovers a specific stable binding site for a luminescent probe on amyloid-beta fibrils through unbiased molecular dynamics, linking binding conformation to luminescence changes.

Findings

Stable binding site identified via simulations

Binding locks probe in all-trans conformation

Conformational restriction correlates with luminescence change

Abstract

A very stable binding site for the interaction between an pentameric oligothiophene and an amyloid-$\beta$(1-42) fibril has been identified by means of non-biased molecular dynamics simulations. In this site, the probe is locked in an all-trans conformation with a Coulombic binding energy of 1,200 kJ/mol due to the interactions between the anionic carboxyl groups of the probe and the cationic $\epsilon$-amino groups in the lysine side chain. Upon binding, the conformationally restricted probes show a pronounced increase in molecular planarity. This is in-line with the observed changes in luminescence properties that serve as the foundation for their use as biomarkers.