Molecular Interactions of Alzheimer's Biomarker FDDNP with Aβ Peptide

Abstract

All-atom explicit solvent model and replica exchange molecular dynamics were used to investigate binding of Alzheimer's biomarker FDDNP to the Aβ10–40 monomer. At low and high concentrations, FDDNP binds with high affinity to two sites in the Aβ10–40 monomer located near the central hydrophobic cluster and in the C-terminal. Analysis of ligand- Aβ10–40 interactions at both concentrations identifies hydrophobic effect as a main binding factor. However, with the increase in ligand concentration the interactions between FDDNP molecules also become important due to strong FDDNP self-aggregation propensity and few specific binding locations. As a result, FDDNP ligands partially penetrate the core of the Aβ10–40 monomer, forming large self-aggregated clusters. Ligand self-aggregation does not affect hydrophobic interactions as a main binding factor or the location of binding sites in Aβ10–40. Using the Aβ10–40 conformational ensemble in ligand-free water as reference, we show that FDDNP induces minor changes in the Aβ10–40 secondary structure at two ligand concentrations studied. At the same time, FDDNP significantly alters the peptide tertiary fold in a concentration-dependent manner by redistributing long-range, side-chain interactions. We argue that because FDDNP does not change Aβ10–40 secondary structure, its antiaggregation effect is likely to be weak. Our study raises the possibility that FDDNP may serve as a biomarker of not only Aβ fibril species, but of monomers as well.