Dataset Information

Binding of Congo red to amyloid protofibrils of the Alzheimer A?(9-40) peptide probed by molecular dynamics simulations.

ABSTRACT: Congo red (CR) is a commonly used histological amyloid dye and a weak amyloid inhibitor. There is currently no experimentally available structure of CR bound to an amyloid fibril and the binding modes, and the mechanisms governing its inhibitory and optical properties are poorly understood. In this work, we present the first, to our knowledge, atomistically detailed picture of CR binding to protofibrils of the Alzheimer A?(9-40) peptide. We identify three major binding modes, with the primary mode residing in the grooves formed by the ?-sheets, and observe a restriction of the torsional rotation of the CR molecule upon binding. Our simulations reveal a novel, to our knowledge, electrostatic steering mechanism that plays an important role in the initial recognition and binding of CR to the positively charged surface residues of the fibril. Our simulations provide new, to our knowledge, insights into the striking spectrophotometric and inhibitory properties of CR. In particular, we show that birefringence upon CR binding is due to the anisotropic orientation of the CR dipoles resulting from the spatial ordering of these molecules in the grooves along the fibril axis. The fluorescent enhancement of the bound CR, in turn, is associated with the torsional restriction of this molecule upon binding.

SUBMITTER: Wu C

PROVIDER: S-EPMC3414877 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Binding of Congo red to amyloid protofibrils of the Alzheimer Aβ(9-40) peptide probed by molecular dynamics simulations.

Wu Chun C Scott Justin J Shea Joan-Emma JE

Biophysical journal 20120801 3

Congo red (CR) is a commonly used histological amyloid dye and a weak amyloid inhibitor. There is currently no experimentally available structure of CR bound to an amyloid fibril and the binding modes, and the mechanisms governing its inhibitory and optical properties are poorly understood. In this work, we present the first, to our knowledge, atomistically detailed picture of CR binding to protofibrils of the Alzheimer Aβ(9-40) peptide. We identify three major binding modes, with the primary mo ...[more]

PMID: 22947871

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Project description:Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-? (A?) monomers and polydisperse, NMR-invisible ('dark') protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of A?, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer's disease. The (15)N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of (15)N transverse relaxation rates ((15)N-R(2)) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional (1)H-(15)N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both A?40 and A?42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of A? fibrils, and might therefore comprise the critical nucleus for fibril formation. The values, however, are significantly larger for the C-terminal residues of A?42 than A?40, which might explain the former's higher propensity for rapid aggregation and fibril formation.

Dataset Information

Binding of Congo red to amyloid protofibrils of the Alzheimer A?(9-40) peptide probed by molecular dynamics simulations.

Publications

Binding of Congo red to amyloid protofibrils of the Alzheimer Aβ(9-40) peptide probed by molecular dynamics simulations.

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