Binding of inositol stereoisomers to model amyloidogenic peptides.

Binding of inositol stereoisomers to model amyloidogenic peptides. Li, G., Rauscher, S., Baud, S., & Pomès, R. The Journal of Physical Chemistry B, 116(3):1111-9, 1, 2012.

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Binding of inositol stereoisomers to model amyloidogenic peptides. [link]

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The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer's disease. scyllo-Inositol is a stereochemistry-dependent in vitro inhibitor of amyloid formation. As the first step to elucidate its mechanism of action, we present molecular dynamics simulations of scyllo-inositol and its inactive stereoisomer, chiro-inositol, with simple peptide models, alanine dipeptide (ADP) and (Gly-Ala)(4). We characterize molecular interactions and compute equilibrium binding constants between inositol and ADP as well as, successively, monomers, amorphous aggregates, and fibril-like β-sheet aggregates of (Gly-Ala)(4). Inositol interacts weakly with all peptide systems considered, with millimolar to molar affinities, and displaces the conformational equilibria of ADP but not of the (Gly-Ala)(4) systems. However, scyllo- and chiro-inositol adopt different binding modes on the surface of β-sheet aggregates. These results suggest that inositol does not inhibit amyloid formation by breaking up preformed aggregates but rather by binding to the surface of prefibrillar aggregates.

@article{
 title = {Binding of inositol stereoisomers to model amyloidogenic peptides.},
 type = {article},
 year = {2012},
 pages = {1111-9},
 volume = {116},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/22091989},
 month = {1},
 day = {26},
 id = {1150b74e-d453-36ef-b1ca-4c7f3fbc5f26},
 created = {2012-02-21T21:45:43.000Z},
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 abstract = {The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer's disease. scyllo-Inositol is a stereochemistry-dependent in vitro inhibitor of amyloid formation. As the first step to elucidate its mechanism of action, we present molecular dynamics simulations of scyllo-inositol and its inactive stereoisomer, chiro-inositol, with simple peptide models, alanine dipeptide (ADP) and (Gly-Ala)(4). We characterize molecular interactions and compute equilibrium binding constants between inositol and ADP as well as, successively, monomers, amorphous aggregates, and fibril-like β-sheet aggregates of (Gly-Ala)(4). Inositol interacts weakly with all peptide systems considered, with millimolar to molar affinities, and displaces the conformational equilibria of ADP but not of the (Gly-Ala)(4) systems. However, scyllo- and chiro-inositol adopt different binding modes on the surface of β-sheet aggregates. These results suggest that inositol does not inhibit amyloid formation by breaking up preformed aggregates but rather by binding to the surface of prefibrillar aggregates.},
 bibtype = {article},
 author = {Li, Grace and Rauscher, Sarah and Baud, Stéphanie and Pomès, Régis},
 doi = {10.1021/jp208567n},
 journal = {The Journal of Physical Chemistry B},
 number = {3}
}

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