Solvent and mutation effects on the nucleation of amyloid $β$-protein folding
Experimental evidence suggests that the folding and aggregation of the amyloid $β$-protein (A$β$) into oligomers is a key pathogenetic event in Alzheimer's disease (AD). Inhibiting the pathologic folding and oligomerization of A$β$ 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$β$, A$β_{21-30}$, 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$β_{21-30}$. 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$β$ folds into pathologic structures. Our results are relevant to understand the mechanism of A$β$ 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.