Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates

Amir Aliyan, Thomas J. Paul, Bo Jiang, Christopher Pennington, Gaurav Sharma, Rajeev Prabhakar, Angel A. Martí

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The aggregation of amyloid-β (Aβ) into insoluble fibrils has been associated with the development of Alzheimer's disease. The study of Aβ aggregation with [Re(CO)3(dppz)(Py)]+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine; Py = pyridine) has led to the observation of an irradiation-induced light-switching response accompanied by the oxidation of the Aβ fibril. Here, we used the photophysical and photochemical properties of this complex, as well as spectroscopic and computational methods, to elucidate molecular binding sites on Aβ fibrils. [Re(CO)3(dppz)(Py)]+ binds to Aβ fibrils with a dissociation constant of 4.2 μM and a binding stoichiometry 2.8:1 (Aβ/complex). Molecular dynamics (MD) simulations predicted binding of [Re(CO)3(dppz)(Py)]+ through a hydrophobic cleft on the fibril axis between Val18 and Phe20. Tandem mass spectrometry analysis indicated that oxidation occurred at Met35, footprinting the place of binding, which is close to the site predicted by the MD simulations. Finding binding sites in Aβ is of great importance for the design of Aβ-binding drugs. Alzheimer's disease is a form of dementia affecting over 44 million people worldwide, and its symptoms include agitation, confusion, and memory loss. This disease is characterized by aggregates of the amyloid-β (Aβ) peptide in the brain. The transition of Aβ from the soluble to the aggregated form is linked to the onset of Alzheimer's disease. Molecules that inhibit Aβ aggregation or quench its harmful effect are highly sought after. However, how molecules bind to Aβ is still uncertain. Aβ aggregates are disordered in nature, preventing the use of common methods for studying structure and binding. To address this, we used a rhenium complex that binds to Aβ. Upon light exposure, this complex produces oxidation on Aβ, leaving a mark at the place of binding. Spectroscopic and computational studies allowed elucidation of locations and binding modes of these molecules on Aβ. This information will guide the production of potent drugs with better binding affinities to Aβ for the treatment of Alzheimer's disease. Aliyan et al. have studied binding sites on amyloid-β fibrils by using a rhenium dipyridophenazine complex. The binding interactions were characterized by spectroscopic and computational methods, which indicated a hydrophobic binding site between Val18 and Phe20 of the amyloid-β fibril. Photoirradiation of the rhenium complex produced oxidation on Met35, leaving a footprint on the fibril, which provides empirical confirmation for the binding site. The identification of molecular binding sites in amyloid-β can guide therapies and drugs design for Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)898-912
Number of pages15
JournalChem
Volume3
Issue number5
DOIs
StatePublished - Nov 9 2017

Fingerprint

Binding sites
Amyloid
Binding Sites
Alzheimer Disease
Rhenium
rhenium
Carbon Monoxide
oxidation
Oxidation
drug
Agglomeration
Molecular Dynamics Simulation
Computational methods
Molecules
Molecular dynamics
Dissociative Disorders
Pharmaceutical Preparations
Light
Confusion
Drug Design

Keywords

  • amyloid β
  • footprinting
  • MS-MS
  • photochemistry
  • rhenium carbonyl complexes
  • ROS

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Environmental Chemistry
  • Chemical Engineering(all)
  • Biochemistry, medical
  • Materials Chemistry

Cite this

Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates. / Aliyan, Amir; Paul, Thomas J.; Jiang, Bo; Pennington, Christopher; Sharma, Gaurav; Prabhakar, Rajeev; Martí, Angel A.

In: Chem, Vol. 3, No. 5, 09.11.2017, p. 898-912.

Research output: Contribution to journalArticle

Aliyan, Amir ; Paul, Thomas J. ; Jiang, Bo ; Pennington, Christopher ; Sharma, Gaurav ; Prabhakar, Rajeev ; Martí, Angel A. / Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates. In: Chem. 2017 ; Vol. 3, No. 5. pp. 898-912.
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