The structures of the E22Δ mutant-type amyloid-ß alloforms and the impact of E22Δ mutation on the structures of the wild-type amyloid-ß alloforms.

Structural differences between the intrinsically disordered fibrillogenic wild-type Aß40 and Aß42 peptides are linked to Alzheimer's disease. Recently, the E22Δ genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22Δ mutant-type Aß40 and Aß42 alloform structures as well as the differences from the wild-type Aß40 and Aß42 alloform structures is currently lacking. In this study, we present the structures of the E22Δ mutant-type Aß40 and Aß42 alloforms as well as the impact of E22Δ mutation on the wild-type Aß40 and Aß42 alloform structures. For this purpose, we performed extensive microsecond-time scale parallel tempering molecular dynamics simulations coupled with thermodynamic calculations. For studying the residual secondary structure component transition stabilities, we developed and applied a new theoretical strategy in our studies. We find that the E22Δ mutant-type Aß40 might have a higher tendency toward aggregation due to more abundant ß-sheet formation in the C-terminal region in comparison to the E22Δ mutant-type Aß42 peptide. More abundant α-helix is formed in the mid-domain regions of the E22Δ mutant-type Aß alloforms rather than in their wild-type forms. The turn structure at Ala21-Ala30 of the wild-type Aß, which has been linked to the aggregation process, is less abundant upon E22Δ mutation of both Aß alloforms. Intramolecular interactions between the N-terminal and central hydrophobic core (CHC), N- and C-terminal, and CHC and C-terminal regions are less abundant or disappear in the E22Δ mutant-type Aß alloform structures. The thermodynamic trends indicate that the wild-type Aß42 tends to aggregate more than the wild-type Aß40 peptide, which is in agreement with experiments. However, this trend is vice versa for the E22Δ mutant-type alloforms. The structural properties of the E22Δ mutant-type Aß40 and Aß42 peptides reported herein may prove useful for the development of new drugs to block the formation of toxic E22Δ mutant-type oligomers by either stabilizing helical or destabilizing ß-sheet structure in the C-terminal region of these two mutant alloforms.

Amyloid-ß peptide structure in aqueous solution varies with fragment size.

Various fragment sizes of the amyloid-ß (Aß) peptide have been utilized to mimic the properties of the full-length Aß peptide in solution. Among these smaller fragments, Aß16 and Aß28 have been investigated extensively. In this work, we report the structural and thermodynamic properties of the Aß16, Aß28, and Aß42 peptides in an aqueous solution environment. We performed replica exchange molecular dynamics simulations along with thermodynamic calculations for investigating the conformational free energies, secondary and tertiary structures of the Aß16, Aß28, and Aß42 peptides. The results show that the thermodynamic properties vary from each other for these peptides. Furthermore, the secondary structures in the Asp1-Lys16 and Asp1-Lys28 regions of Aß42 cannot be completely captured by the Aß16 and Aß28 fragments. For example, the ß-sheet structures in the N-terminal region of Aß16 and Aß28 are either not present or the abundance is significantly decreased in Aß42. The α-helix and ß-sheet abundances in Aß28 and Aß42 show trends--to some extent--with the potential of mean forces but no such trend could be obtained for Aß16. Interestingly, Arg5 forms salt bridges with large abundances in all three peptides. The formation of a salt bridge between Asp23-Lys28 is more preferred over the Glu22-Lys28 salt bridge in Aß28 but this trend is vice versa for Aß42. This study shows that the Asp1-Lys16 and Asp1-Lys28 regions of the full length Aß42 peptide cannot be completely mimicked by studying the Aß16 and Aß28 peptides.

Luminescence properties and quenching mechanisms of Ln(Tf2N)3 complexes in the ionic liquid bmpyr Tf2N.

The emission properties, including luminescence lifetimes, of the lanthanide complexes Ln(Tf(2)N)(3) (Tf(2)N = bis(trifluoromethanesulfonyl)amide); Ln(3+) = Eu(3+), Tm(3+), Dy(3+), Sm(3+), Pr(3+), Nd(3+), Er(3+)) in the ionic liquid bmpyr Tf(2)N (bmpyr = 1-n-butyl-1-methylpyrrolidinium) are presented. The luminescence quantum efficiencies, η, and radiative lifetimes, τ(R), are determined for Eu(3+)((5)D(0)), Tm(3+)((1)D(2)), Dy(3+)((4)F(9/2)), Sm(3+)((4)G(5/2)), and Pr(3+)((3)P(0)) emission. The luminescence lifetimes in these systems are remarkably long compared to values typically reported for Ln(3+) complexes in solution, reflecting weak vibrational quenching. The 1.5 µm emission corresponding to the Er(3+) ((4)I(13/2)→(4)I(15/2)) transition, for example, exhibits a lifetime of 77 µs. The multiphonon relaxation rate constants are determined for 10 different Ln(3+) emitting states, and the trend in multiphonon relaxation is analyzed in terms of the energy gap law. The energy gap law does describe the general trend in multiphonon relaxation, but deviations from the trend are much larger than those normally observed for crystal systems. The parameters determined from the energy gap law analysis are consistent with those reported for crystalline hosts. Because Ln(3+) emission is known to be particularly sensitive to quenching by water in bmpyr Tf(2)N, the binding properties of water to Eu(3+) in solutions of Eu(Tf(2)N)(3) in bmpyr Tf(2)N have been quantified. It is observed that water introduced into these systems binds quantitatively to Ln(3+). It is demonstrated that Eu(Tf(2)N)(3) can be used as a reasonable internal standard, both for monitoring the dryness of the solutions and for estimating the quantum efficiencies and radiative lifetimes for visible-emitting [Ln(Tf(2)N)(x)](3-x) complexes in bmpyr Tf(2)N.