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Effects of oxidation, pH and lipids on amyloidogenic peptide structure: implications for fibril formation?

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Abstract

We have performed experimental and computational studies to investigate the influences of phospholipids, methionine oxidation and acidic pH on amyloid fibril formation by a peptide derived from human apolipoprotein C-II (apoC-II), a known component of proteinaceous atherosclerotic plaques. Fibril growth monitored by thioflavin T fluorescence revealed inhibition under lipid-rich and oxidising conditions. We subsequently performed fully-solvated atomistic molecular dynamics (MD) simulations of the peptide monomer to study its conformations under both fibril favouring (neutral and low pH) and inhibiting (lipid-rich and oxidising) conditions. Examination of the chain topology, backbone hydrogen-bonding patterns and aromatic sidechain orientations of the peptide under different conditions reveals that, while the peptide adopts similar structures under the fibril-favouring conditions, significantly different structures are obtained under fibril-disruptive conditions. Based on our results, we advance hypotheses for the roles of peptide conformation on aggregation and fibrillisation propensities.

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Acknowledgments

We acknowledge the Australian Partnership for Advanced Computing (APAC) and Victorian Partnership for Advanced Computing (VPAC) for provision of computational resources, and the latter for provision of funds under the eResearch grants scheme. We also thank our colleagues at RMIT University (Sue Legge, Nevena Todorova and Akin Budi) for many helpful discussions.

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Authors and Affiliations

  1. School of Applied Sciences, RMIT University, GPO Box 2476V, Melbourne, VIC, 3001, Australia

    Andrew Hung & Irene Yarovsky

  2. Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, 3010, Australia

    Michael D. W. Griffin & Geoffrey J. Howlett

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  1. Andrew Hung
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  2. Michael D. W. Griffin
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  3. Geoffrey J. Howlett
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  4. Irene Yarovsky
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Correspondence to Irene Yarovsky.

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Hung, A., Griffin, M.D.W., Howlett, G.J. et al. Effects of oxidation, pH and lipids on amyloidogenic peptide structure: implications for fibril formation?. Eur Biophys J 38, 99–110 (2008). https://doi.org/10.1007/s00249-008-0363-3

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  • DOI: https://doi.org/10.1007/s00249-008-0363-3

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