Solvent and mutation effects on the nucleation of amyloid   $\beta$-protein folding
  Experimental evidence suggests that the folding and aggregation of the amyloid $\beta$-protein (A$\beta$) into oligomers is a key pathogenetic event in Alzheimer's disease (AD). Inhibiting the pathologic folding and oligomerization of A$\beta$ could be effective in the prevention and treatment of AD. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of A$\beta$, A$\beta_{21-30}$, shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis--Dutch type, [Gln22]A$\beta_{21-30}$. We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys28 and either Glu22 or Asp23 are important in the formation of a loop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; (iv) the ``Dutch'' peptide in water, in contrast to the wild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting that loop stability is a critical factor in determining whether A$\beta$ folds into pathologic structures. Our results are relevant to understand the mechanism of A$\beta$ peptide folding in different environments, such as intra- and extracellular milieus or cell membranes, and how amino acid substitutions linked to familial forms of amyloidosis cause disease. 
Luis Cruz, Brigita Urbanc, Jose M. Borreguero, Noel D. Lazo, David B.   Teplow and H. Eugene Stanley