The 40-42 residue amyloid beta-protein (Abeta) plays a central role in the pathogenesis
of Alzheimer's disease (AD). Of the two main alloforms, Abeta40 and Abeta42, the longer
Abeta42 is linked particularly strongly to AD. Despite the relatively small two amino
acid length difference in primary structure, in vitro studies demonstrate that Abeta40
and Abeta42 oligomerize through distinct pathways. Recently, a discrete molecular
dynamics (DMD) approach combined with a four-bead protein model recapitulated the
differences in Abeta40 and Abeta42 oligomerization and led to structural predictions
amenable to in vitro testing. Here, the same DMD approach is applied to elucidate
folding of Abeta40, Abeta42, and two mutants, [G22]Abeta40 and [G22]Abeta42, 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 beta-strand content in Abeta42 monomer, as determined using circular
dichroism (CD) spectroscopy. In agreement with these CD data, we show that at physiological
temperatures, the average beta-strand content in both alloforms increases with temperature.
Our results predict that the average beta-strand propensity should decrease in both
alloforms at temperatures higher than approximately 370 K. At physiological temperatures,
both Abeta40 and Abeta42 adopt a collapsed-coil conformation with several short beta-strands
and a small (<1%) amount of alpha-helical structure. At slightly above physiological
temperature, folded Abeta42 monomers display larger amounts of beta-strand than do
Abeta40 monomers. At increased temperatures, more extended conformations with a higher
amount of beta-strand (approximately < 30%) structure are observed. In both alloforms,
a beta-hairpin at A21-A30 is a central folding region. We observe three additional
folded regions: structure 1, a beta-hairpin at V36-A42 that exists in Abeta42 but
not in Abeta40; structure 2, a beta-hairpin at R5-H13 in Abeta42 but not in Abeta40;
and structure 3, a beta-strand A2-F4 in Abeta40 but not Abeta42. At physiological
temperatures, the Arctic mutation, E22G, disrupts contacts in the A21-A30 region of
both [G22]Abeta 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]Abeta40 by preventing the formation of structure 3 observed
in Abeta40 but not Abeta42, thereby reducing the structural differences between [G22]Abeta40
and [G22]Abeta42 at the N-terminus. [G22]Abeta40 is characterized by a significantly
increased amount of average beta-strand relative to the other three peptides due to
an induced beta-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 Abeta42, suggesting that both Arctic Abeta peptides might assemble into
structures similar to toxic Abeta42 oligomers.