Simulations of monomeric amyloid β-peptide (1–40) with varying solution conditions and oxidation state of Met35: Implications for aggregation

•We modeled 4 different solution environments with oxidized and reduced Aβ monomers.•Met35ox affects aggregation propensity based on secondary structure changes.•pH and ionic strength affect aggregation tendencies more in Aβ40-Met35ox than in Aβ40.

The amyloid β-peptide (Aβ) is a 40–42 residue peptide that is the principal toxic species in Alzheimer’s disease (AD). The oxidation of methionine-35 (Met35) to the sulfoxide form (Met35ox) has been identified as potential modulator of Aβ aggregation. The role Met35ox plays in Aβ neurotoxicity differs among experimental studies, which may be due to inconsistent solution conditions (pH, buffer, temperature). We applied atomistic molecular dynamics (MD) simulations as a means to probe the dynamics of the monomeric 40-residue alloform of Aβ (Aβ40) containing Met35 or Met35ox in an effort to resolve the conflicting experimental results. We found that Met35 oxidation decreases the β-strand content of the C-terminal hydrophobic region (residues 29–40), with a specific effect on the secondary structure of residues 33–35, thus potentially impeding aggregation. Further, there is an important interplay between oxidation state and solution conditions, with pH and salt concentration augmenting the effects of oxidation. The results presented here serve to rationalize the conflicting results seen in experimental studies and provide a fundamental biophysical characterization of monomeric Aβ40 dynamics in both reduced and oxidized forms, providing insight into the biochemical mechanism of Aβ40 and oxidative stress related to AD.

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