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Molecular interactions of Alzheimer's biomarker FDDNP with A? peptide.

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

SUBMITTER: Lockhart C

PROVIDER: S-EPMC3514529 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Lockhart Christopher C Klimov Dmitri K DK

Biophysical journal 20121201 11

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 concentrat ...[more]

PMID: 23283233

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Project description:Currently, there are very limited pharmaceutical interventions for Alzheimer's disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer's disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40-42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1-42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.

Dataset Information

Molecular interactions of Alzheimer's biomarker FDDNP with A? peptide.

Publications

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

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