| Summary: | Oligomers of amyloid β-protein (Aβ) play a central role In the pathology of Alzheimer's disease. Of the two predominant Aß alloforms, Aβ1-40 and Aβ1-42, Aβ1-42 is more strongly implicated In the disease. We elucidated the structural characteristics of oligomers of Aβ1-40 and Aβ-42 and their Arctic mutants, [E22G]Aβ1-40 and [E22G]Aβ 1-42. We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were In agreement with prior experimental findings. Unlike Aβ1-40, Aβ1-42 had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higherorder oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]Aβ1-40 formed paranuclei with a similar propensity to that of Aβ1-42. Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophllic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-termlnal region played a dominant role In Aβ1-42 oligomer formation whereas Aβ1-40 ollgomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-termlnal region A2-F4 played a prominent role in Aβ1-40 ollgomerization but did not contribute to the ollgomerization of Aβ1-42 or the Arctic mutants. The oligomer structure of both Arctic peptides resembled Aβ1-42 more than Aβ1-40, consistent with their potentially more toxic nature. © 2010 American Chemical Society.
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