| Summary: | The 40-42 residue amyloid β-protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Of the two main alloforms, Aβ40 and Aβ42, the longer Aβ42 is linked particularly strongly to AD. Despite the relatively small two amino acid length difference in primary structure, in vitro studies demonstrate that Aβ40 and Aβ42 oligomerize through distinct pathways. Recently, a discrete molecular dynamics (DMD) approach combined with a four-bead protein model recapitulated the differences in Aβ40 and Aβ42 oligomerization and led to structural predictions amenable to in vitro testing. Here, the same DMD approach is applied to elucidate folding of Aβ40, Aβ42, and two mutants, [G22]Aβ40 and [G22]Aβ42, which cause a familial ("Arctic") form of AD. The implicit solvent in the DMD approach is modeled by amino acid-specific hydropathic and electrostatic interactions. The strengths of these effective interactions are chosen to best fit the temperature dependence of the average β-strand content in Aβ42 monomer, as determined using circular dichroism (CD) spectroscopy. In agreement with these CD data, we show that at physiological temperatures, the average β-strand content in both alloforms increases with temperature. Our results predict that the average β-strand propensity should decrease in both alloforms at temperatures higher than ∼370 K. At physiological temperatures, both Aβ40 and Aβ42 adopt a collapsed-coil conformation with several shortβ-strands and a small (<1%) amount of a-helical structure. At slightly above physiological temperature, folded Aβ42 monomers display larger amounts of β-strand than do Aβ40 monomers. At increased temperatures, more extended conformations with a higher amount of β-strand (≲30%) structure are observed. In both alloforms, a β-hairpin at A21-A30 is a central folding region. We observe three additional folded regions: structure 1, a β-hairpin at V36-A42 that exists in Aβ42 but not in Aβ40; structure 2, a β-hairpin at R5-H13 in Aβ42 but not in Aβ40; and structure 3, a β-strand A2-F4 in Aβ40 but not Aβ42. At physiological temperatures, the Arctic mutation, E22G, disrupts contacts in the A21-A30 region of both [G22]Aβ peptides, resulting in a less stable main folding region relative to the wild type peptides. The Arctic mutation induces a significant structural change at the N-terminus of [G22]β340 by preventing the formation of structure 3 observed in Aβ40 but not Aβ42, thereby reducing the structural differences between [G22]Aβ40 and [G22]Aβ42 at the N-terminus. [G22]Aβ40 is characterized by a significantly increased amount of average β-strand relative to the other three peptides due to an induced β-hairpin structure at R5-H13, similar to structure 2. Consequently, the N-terminal folded structure of the Arctic mutants closely resembles the N-terminal structure of Aβ42, suggesting that both Arctic Aβ peptides might assemble into structures similar to toxic Aβ42 oligomers. © 2008 American unemical society.
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