Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22).

Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22). Li, G. & Pomès, R. The Journal of Physical Chemistry B, 117(22):6603–6613, 5, 2013.

Paper

Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22). [link]

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Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Aβ42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Aβ fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Aβ(16-22), an amyloid-forming peptide fragment of full-length Aβ, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to β-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Aβ protofibrils and disrupts their lateral stacking into amyloid fibrils.

@article{
 title = {Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22).},
 type = {article},
 year = {2013},
 pages = {6603–6613},
 volume = {117},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23627280},
 month = {5},
 day = {23},
 id = {c149a202-0c76-316c-9450-9b0e81ae516f},
 created = {2013-06-06T21:07:22.000Z},
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 last_modified = {2017-03-28T17:10:06.277Z},
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 abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Aβ42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Aβ fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Aβ(16-22), an amyloid-forming peptide fragment of full-length Aβ, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to β-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Aβ protofibrils and disrupts their lateral stacking into amyloid fibrils.},
 bibtype = {article},
 author = {Li, Grace and Pomès, Régis},
 doi = {10.1021/jp311350r},
 journal = {The Journal of Physical Chemistry B},
 number = {22}
}

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