G37V mutation of Aß42 induces a nontoxic ellipse-like aggregate: An in vitro and in silico study.

The glycine zipper motif at the C-terminus of the ß-amyloid (Aß) peptide have been shown to strongly influence the formation of neurotoxic aggregates. A previous study showed that the G37L mutation dramatically reduces the Aß toxicity in vivo and in vitro. However, the primary cause and mechanism of the glycine zipper motif on Aß properties remain unknown. To gain molecular insights into the impact of glycine zipper on Aß properties, we substituted the residue 37 of Glycine by Valine and studied the structural and biochemical properties of G37V mutation, Aß42(37V), by using in vitro and in silico approaches. Unlike G37L mutation, the G37V mutation reduced toxicity substantially but did not significantly accelerate the aggregation rate or change the content of secondary structures. Further TEM analyses showed that the G37V mutation formed an ellipse-like aggregate rather than a network-like fibril as wild type or G37L mutation of Aß42 form. This different aggregation morphology may be highly linked with the reduction of toxicity. To gain the insight for the different properties of Aß42(37V), we studied the structure of Aß42 and G37V mutation using the replica exchange molecular dynamics simulation. Our results demonstrate that although the overall secondary structure population is similar with Aß42 and Aß42(G37V), Aß42(G37V) shows an increase in the ß-turn and ß-hairpin at residues 36-37 and the flexibility of the Asp23-Lys28 salt bridge. These unique structural features may be the possible reason to account for the ellipse-like morphology.

Impact of Mutations at C-Terminus on Structures and Dynamics of Aß40 and Aß42: A Molecular Simulation Study.

Alzheimer's disease is presumed to be caused by the formation of intracellular plaques of amyloid ß (Aß) peptides inside neurons. The most abundant Aß forms are Aß40 and Aß42 comprising, respectively, 40 and 42 residues. Recent experiments showed that the triple Gly33Val-Val36Pro-Gly38Val (VPV) mutation causes Aß42 to become "super-Aß42" with elevated aggregation rates and toxicity. Upon VPV mutation, oligomerization pathways of Aß40 become similar to those of the Aß42 wild type. It was hypothesized that the super behavior of Aß42 occurs due to an enhanced content of the ß-turn and ß-hairpin, centered at residues 36-37, and the similarity in oligomerization pathways of Aß40-VPV and Aß42-WT comes from the increased ß-turn population. As this is based on simulation of the truncated fragments, this hypothesis may not be valid for the full-length case, motivating us to perform all-atom molecular dynamics simulations for full-length Aß sequences. We showed that the results obtained for truncated peptides fall short in explaining the similarity of self-assembly pathways of Aß40-VPV and Aß42-WT. Instead, we propose that the similarity is due to not only increased ß-turn population but also due to the elevated ß-structure of the entire sequence. Similar to VPV, the Gly33Val-Val36Asn-Gly38Leu mutation enhances the ß-structure and the C-terminal ß-turn making the behavior of Aß40 similar to that of Aß42-WT.