A left‐handed 3₁ helical conformation in the Alzheimer Aβ(12–28) peptide

Abstract

We show for the ¢rst time that the secondary structure of the Alzheimer L L-peptide is in a temperature-dependent equilibrium between an extended left-handed 3 1 helix and a £exible random coil conformation. Circular dichroism spectra, recorded at 0.03 mM peptide concentration, show that the equilibrium is shifted towards increasing left-handed 3 1 helix structure towards lower temperatures. High resolution nuclear magnetic resonance (NMR) spectroscopy has been used to study the Alzheimer peptide fragment AL L(12^28) in aqueous solution at 0 ‡C and higher temperatures. NMR translation di¡usion measurements show that the observed peptide is in monomeric form. The chemical shift dispersion of the amide protons increases towards lower temperatures, in agreement with the increased population of a well-ordered secondary structure. The solvent exchange rates of the amide protons at 0 ‡C and pH 4.5 vary within at least two orders of magnitude. The lowest exchange rates (0.03^0.04 min 31 ) imply that the corresponding amide protons may be involved in hydrogen bonding with neighboring side chains. ß

Preferred peptide backbone conformations in the unfolded state revealed by the structure analysis of alanine-based (AXA) tripeptides in aqueous solution

“…Jarvet et al (43) investigated A␤ [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] by CD and NMR and identified a substantial PPII population. We have recently arrived at a similar conclusion for the longer and more representative fragment A␤ by comparing the experimentally obtained amide IЈ band profile of the anisotropic Raman spectrum with simulation for various conformations assignable to the left-handed quadrant of the Ramachandran plot (44).…”

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

“…In order to stabilize the monomeric form of the peptide and reduce aggregation, SDS-d 25 micelles (SDS ¼ sodium dodecyl sulfate) were employed (39)(40)(41)(42). At this condition, the Aβ monomer adopts an α-helical conformation, which has been observed in solution and in contact with other biological molecules and may contribute to initial aggregation pathways leading to the formation of oligomers that have been proposed as the neurotoxic species in AD (5,(43)(44)(45)(46)(47). Therefore, the investigation of the possible interactions with the Aβ monomer using this model is valuable in evaluating the efficiency of our compounds to target and interact with Aβ species.…”

Temperature‐dependent structural changes in intrinsically disordered proteins: Formation of α‒helices or loss of polyproline II?

“…[20][21][22][23][24][25][26] This suggests that many IDPs undergo a structural change with increasing temperature. Different models have been put forward to explain this observation; however, the data do not decisively determine which explanation is correct, mainly because of the lack of atomic resolution information.…”

“…Most of these studies have identified structural changes upon heating that were interpreted mostly as formation of a-helices and to a minor extent to a loss of PPII structure. [20][21][22][23][24][25][26] The interpretation of the changes observed by CD spectroscopy is ambiguous. This is caused by the low resolution of this technique and the fact that structural changes in different segments may have spectroscopic contributions that cancel each other's signal.…”