Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils |
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Authors: | Cheon Mookyung Chang Iksoo Mohanty Sandipan Luheshi Leila M Dobson Christopher M Vendruscolo Michele Favrin Giorgio |
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Affiliation: | Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. |
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Abstract: | Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils. |
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