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Amyloid-protein (A    ) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, Aand A    , results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of Aand Aassembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD–derived Aand Amonomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower-strand propensities than those predicted by DMD. Fully atomistic Aand Amonomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of Adimers indicated a larger conformational variability in comparison to that of Adimers. Adimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to Adimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of Adimers and was significantly lower than in Adimers. The potential relevance of the three positively charged amino acids in mediating the Aoligomer toxicity is discussed in the light of available experimental data.

Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study