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Effects of G33A and G33I mutations on the structures of monomer and dimer of the amyloid-β fragment 29-42 by replica exchange molecular dynamics simulations.

The early formed oligomers of amyloid-β proteins with 40 and 42 amino acids are believed to be the culprits of Alzheimer's disease. Aβ1-42 peptides with alanine and isoleucine mutations of glycine 33 are known to be much less toxic than the wild-type Aβ1-42 and promote the aggregation process in vitro. The fragment Aβ29-42 has also been shown to form fibrils, disrupt Aβ1-42 oligomerization, and inhibit Aβ1-42-induced neurotoxicity. As a first step toward understanding the impact of G33A and G33I mutations on the earliest steps along the Aβ1-42 aggregation pathway, we have studied the structures of the monomer and dimer of Aβ29-42 and its two G33 variants using coarse-grained replica exchange molecular dynamics simulations. These simulations, totaling 15 μs, indicate that both substitutions impact the conformational ensemble of Aβ29-42. For the monomer, the population of the β-hairpin is high for wild-type Aβ29-42, but marginal for Aβ29-42 G33I mutant. The three dimers are also stabilized by different patterns of interaction. The data are discussed in terms of the differences in the aggregation characteristics between wild-type Aβ1-42 and its two G33A and G33I variants.