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On the origin of the stronger binding of PIB over thioflavin T to protofibrils of the Alzheimer amyloid-? peptide: a molecular dynamics study.

ABSTRACT: Pittsburgh compound B (PIB) is a neutral derivative of the fluorescent dye Thioflavin T (ThT), which displays enhanced hydrophobicity and binding affinity to amyloid fibrils. We present molecular dynamics simulations of binding of PIB and ThT to a common cross-?-subunit of the Alzheimer Amyloid-? peptide (A?). Our simulations of binding to A?(9-40) protofibrils show that PIB, like ThT, selectively binds to the hydrophobic or aromatic surface grooves on the ?-sheet surface along the fibril axis. The lack of two methyl groups and charge in PIB not only improves its hydrophobicity but also leads to a deeper insertion of PIB compared to ThT into the surface grooves. This significantly increases the steric, aromatic, and hydrophobic interactions, and hence leads to stronger binding. Simulations on protofibrils consisting of the more-toxic A?(17-42) revealed an additional binding mode in which PIB and ThT insert into the channel that forms in the loop region of the protofibril, sandwiched between two sheet layers. Our simulations indicate that the rotation between the two ring parts of the dyes is significantly more restricted when the dyes are bound to the surface of the cross-?-subunits or to the channel inside the A?(17-42) cross-?-subunit, compared with free solution. The specific conformations of the dyes are influenced by small chemical modifications (ThT versus PIB) and by the environment in which the dye is placed.

SUBMITTER: Wu C

PROVIDER: S-EPMC3043208 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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On the origin of the stronger binding of PIB over thioflavin T to protofibrils of the Alzheimer amyloid-β peptide: a molecular dynamics study.

Wu Chun C Bowers Michael T MT Shea Joan-Emma JE

Biophysical journal 20110301 5

Pittsburgh compound B (PIB) is a neutral derivative of the fluorescent dye Thioflavin T (ThT), which displays enhanced hydrophobicity and binding affinity to amyloid fibrils. We present molecular dynamics simulations of binding of PIB and ThT to a common cross-β-subunit of the Alzheimer Amyloid-β peptide (Aβ). Our simulations of binding to Aβ(9-40) protofibrils show that PIB, like ThT, selectively binds to the hydrophobic or aromatic surface grooves on the β-sheet surface along the fibril axis. ...[more]

PMID: 21354405

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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.

Project description:BACKGROUND: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of ?-amyloid (A?), activation of astrocytes and microglia and disruption of cholinergic neurotransmission. Since the topographical characteristics of these different pathological processes in AD brain and how these relate to each other is not clear, this motivated further exploration using binding studies in postmortem brain with molecular imaging tracers. This information could aid the development of specific biomarkers to accurately chart disease progression. RESULTS: In vitro binding assays demonstrated increased [³H]-PIB (fibrillar A?) and [³H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [³H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [³H]-nicotine (?4?2 nicotinic acetylcholine receptor (nAChR)) binding in the FC of AD cases compared to age-matched controls. Quantitative autoradiography binding studies were also performed to investigate the regional laminar distributions of [³H]-L-deprenyl, [³H]-PIB as well as [¹²?I]-?-bungarotoxin (?7 nAChRs) and [³H]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [³H]-PIB binding in all layers and [³H]-deprenyl in superficial layers of the FC. In contrast, [³H]-PIB showed low binding to fibrillar A?, but [³H]-deprenyl high binding to activated astrocytes throughout the HIP. The [³H]-PIB binding was also low and the [³H]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [³H]-nicotine binding was observed in all layers of the frontal cortex in comparison to layers in the medial temporal gyrus, insular cortex and hippocampus. Immunohistochemical detection in the AD case revealed abundant glial fibrillary acidic protein positive (GFAP+) reactive astrocytes and ?7 nAChR expressing GFAP+ astrocytes both in the vicinity and surrounding A? neuritic plaques in the FC and HIP. Although fewer A? plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained A?-positive (6 F/3D) granules within their somata. CONCLUSIONS: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar A?, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.

Dataset Information

On the origin of the stronger binding of PIB over thioflavin T to protofibrils of the Alzheimer amyloid-? peptide: a molecular dynamics study.

Publications

On the origin of the stronger binding of PIB over thioflavin T to protofibrils of the Alzheimer amyloid-β peptide: a molecular dynamics study.

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