Molecular Mechanisms of Alzheimer’s Biomarker FDDNP Binding to Aβ Amyloid Fibril

Abstract

Using isobaric-isothermal replica exchange molecular dynamics and the all-atom explicit water model, we examined the binding of FDDNP biomarkers to the Aβ amyloid fibril fragment. Our results can be summarized as follows. First, FDDNP ligands bind with high affinity to the Aβ fibril, and the hydrophobic effect together with π-stacking interactions are the dominant factors governing FDDNP binding. In comparison, electrostatic interactions and hydrogen bonding play a minor role. Second, our simulations reveal a strong tendency of bound FDDNP molecules for self-aggregation. Accordingly, about two-thirds of all bound ligands form aggregated clusters of various sizes, and ligand-ligand interactions make considerable contribution to FDDNP binding. Third, FDDNP ligands bind to two distinct sites on the Aβ fibril. Primary binding sites (NT) are located at the N-terminals of Aβ10-40 peptides, whereas secondary ones (CE) occur on the concave fibril edge near fibril channels. The NT sites are characterized by strong hydrophobic and π-stacking interactions, favorable binding entropy resulting from multiple FDDNP binding orientations and propensity for self-aggregation but relatively weak van der Waals interactions. In contrast, the CE sites offer stronger van der Waals binding interactions but weaker hydrophobic and aromatic interactions and less favorable binding entropy. By comparing our data with previous studies, we suggest that the primary binding locations identified by us are likely to occur in other Aβ fibril polymorphic structures. We also show that FDDNP binds via distinct mechanisms to Aβ fibrils and monomers. We argue that FDDNP binds with stronger affinity to benign Aβ monomers than to the fibrils, raising questions about the ability of FDDNP to selectively label amyloid deposits.

Repurposing Triphenylmethane Dyes to Bind to Trimers Derived from Aβ

“…The dye Congo red has been used to stain amyloid plaques in tissue for nearly a century, while thioflavin T and thioflavin S have been used for several decades as both probes of amyloid plaques and tools to monitor the aggregation of amyloid-forming proteins into fibrils. − New life has been breathed into these chemical probes through the creative application of their selectivity for amyloid plaques. For example, homologues of Congo red have been used to block amyloid fibril formation, radio-labeled homologues of thioflavin T are currently used in PET imaging diagnostic tests of Alzheimer’s disease, and combinatorial fluorescent molecular sensors based around thioflavin T have enabled differentiation among aggregates of Aβ. − High-resolution structures of fibrils and fibril–dye complexes, coupled with molecular dynamics simulations, have revealed structural bases of this molecular recognition, wherein planar aromatic dyes lie parallel to the fibril axis and pack against hydrophobic residues displayed on the fibril surface. − These structures have guided the design of other small molecules that bind to amyloid fibrils …”

Cholesterol Changes the Mechanisms of Aβ Peptide Binding to the DMPC Bilayer

“…To identify cholesterol binding sites in the Aβ peptide, we applied the method developed previously by our group . Briefly, we define a binding site as a set of Aβ amino acids i that satisfy two conditions.…”

The Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers

“…However, because the association of such PET tracers to core sites may involve very large time scales, it is difficult to model them using traditional force field-based computational approaches. We recollect that there indeed exist some studies that have focused on the amyloid binding mechanism of various PET tracers using the molecular dynamics approach, but due to the limited time scale, it was only possible to address surface binding sites in these studies. , In an earlier study, the present authors carried out integrated molecular docking and molecular dynamics followed by molecular mechanics generalized Born surface area (MM/GBSA) based free energy calculations, where all possible binding sites (which include two core sites, one entry cleft, and two surface sites) were identified for the THT and AZD-2184 molecules . It was possible to explain the binding profiles for these two molecules, and in addition, larger binding affinity of the latter molecule was explained.…”