title: Simulations of monomeric amyloid β-peptide (1-40) with varying solution conditions and oxidation state of Met35: implications for aggregation.
abstract: 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 (Met35(ox)) has been identified as potential modulator of Aβ aggregation. The role Met35(ox) 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 Met35(ox) 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.
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Brown
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Lemkul
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schaum
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: drbevan@vt.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Bevan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008715:Methionine / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C442220:amyloid beta-protein (2-42); D008715:Methionine
keywords: Amyloid-β; Methionine oxidation; Modeling; Molecular dynamics simulations; Protein folding