Title: Structural Dynamics of Iowa, Dutch, and Arctic Mutations of the 21-30 Fragment of Amyloid Beta under Aqueous Salt Environments
Abstract: The amyloid β protein (Aβ) has been implicated in the pathogenesis of Alzheimer's disease. Previous in vitro experiments have shown that the central Aβ(21-30) fragment may have special importance because it may act as a folding nucleus of the full-length protein. Recently, experiments of the full-length wild type (WT) peptide under aqueous salt environments have revealed varied responses in both the structure and growth of aggregates of the full-length peptide under these environments. Here we use all-atom molecular dynamics simulations of monomeric Aβ(21-30) to examine pre-aggregate structural alterations under similar dissolved salt conditions (CaCl2 and KCl). Further, we make use of the wild-type and three common mutations of the decapeptide (Arctic[E22/G22], Dutch[E22/Q22], and Iowa[D23/N23]) to explore the possible dependence of charged side-chain and salt-ion interactions in driving structural changes under aqueous salt environments. Our results indicate that the production and stability of open (random-coil) structures is enhanced under CaCl2 for the wild-type decapeptide, and both Dutch and Iowa mutations; while KCl environments enhanced the production of turn structures for wild-type and β-structures for the Iowa and Dutch mutations. Additionally, we present a possible explanation for these differences in structural response as a combination of volume exclusion, ion-residue interactions, and ion effects on the hydration of the decapeptide.