Experimental findings suggest that oligomeric forms of the amyloid ␤ protein (A␤) play a critical role in Alzheimer's disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, A␤40 and A␤42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. A␤40 forms significantly more dimers than A␤42, whereas pentamers are significantly more abundant in A␤42 relative to A␤40. Structure analysis reveals a turn centered at Gly-37-Gly-38 that is present in a folded A␤42 monomer but not in a folded A␤40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in A␤42 pentamer formation. A␤ pentamers have a globular structure comprising hydrophobic residues within the pentamer's core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of A␤40 pentamers are more spatially restricted than A␤42 pentamers. A␤40 pentamers form a ␤-strand structure involving Ala-2-Phe-4, which is absent in A␤42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the A␤42 pentamer being more exposed and thus more prone to form larger oligomers.Alzheimer's disease ͉ discrete molecular dynamics ͉ four-bead protein model ͉ oligomer formation T he amyloid ␤-protein (A␤) has been strongly linked to the etiology and pathogenesis of Alzheimer's disease (AD). A␤ assembles into amyloid fibrils and smaller, oligomeric assemblies. Experimental and clinical findings suggest that protofibrillar intermediates (1-3) and oligomeric forms (4-13) of A␤ may be particularly important. If so, elucidating the structures of these A␤ oligomers and the mechanisms of their formation is critical for developing therapeutic agents. Unlike proteins with stable folds, A␤ oligomers are metastable. They cannot be crystallized for x-ray diffraction studies nor can they be easily studied by using solutionphase NMR. Monomers and oligomers are also in dynamic equilibrium, which makes the study of pure populations of conformers using classical biophysical techniques difficult.A␤ exists in two predominant forms, 40 (A␤40) or 42 (A␤42) amino acids in length. Of the two, A␤42 is associated most strongly with an increased risk for AD, is more neurotoxic, and forms fibrils significantly faster. Recent experiments demonstrated that A␤ oligomers can be covalently cross-linked, and therefore stabilized, by using the technique of photo-induced cross-linking of unmodified proteins (PICUP) (14). During PICUP coupled with si...

Oligomers of amyloid β-protein (Aβ) play a central role in the pathology of Alzheimer’s disease. Of the two predominant Aβ 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 Aβ1–42 and their Arctic mutants, [E22G]Aβ1–40 and [E22G]Aβ1–42. 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 higher-order 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 hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in Aβ1–42 oligomer formation whereas Aβ1–40 oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in Aβ1–40 oligomerization but did not contribute to the oligomerization 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.