Molecular interactions of Alzheimer's biomarker FDDNP with Aβ peptide.

All-atom explicit solvent model and replica exchange molecular dynamics were used to investigate binding of Alzheimer's biomarker FDDNP to the Aβ(10-40) monomer. At low and high concentrations, FDDNP binds with high affinity to two sites in the Aβ(10-40) monomer located near the central hydrophobic cluster and in the C-terminal. Analysis of ligand- Aβ(10-40) 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 Aβ(10-40) 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 Aβ(10-40). Using the Aβ(10-40) conformational ensemble in ligand-free water as reference, we show that FDDNP induces minor changes in the Aβ(10-40) 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 Aβ(10-40) 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.