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Methionine Oxidation Changes the Mechanism of A? Peptide Binding to the DMPC Bilayer.

ABSTRACT: Using all-atom explicit solvent replica exchange molecular dynamics simulations with solute tempering, we study the effect of methionine oxidation on A?10-40 peptide binding to the zwitterionic DMPC bilayer. By comparing oxidized and reduced peptides, we identified changes in the binding mechanism caused by this modification. First, Met35 oxidation unravels C-terminal helix in the bound peptides. Second, oxidation destabilizes intrapeptide interactions and expands bound peptides. We explain these outcomes by the loss of amphiphilic character of the C-terminal helix due to oxidation. Third, oxidation "polarizes" A? binding to the DMPC bilayer by strengthening the interactions of the C-terminus with lipids while largely releasing the rest of the peptide from bilayer. Fourth, in contrast to the wild-type peptide, oxidized A? induces significantly smaller bilayer thinning and drop in lipid density within the binding footprint. These observations are the consequence of mixing oxidized peptide amino acids with lipids promoted by enhanced A? conformational fluctuations. Fifth, methionine oxidation reduces the affinity of A? binding to the DMPC bilayer by disrupting favorable intrapeptide interactions upon binding, which offset the gains from better hydration. Reduced binding affinity of the oxidized A? may represent the molecular basis for its reduced cytotoxicity.

SUBMITTER: Lockhart C

PROVIDER: S-EPMC6459879 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer.

Lockhart Christopher C Smith Amy K AK Klimov Dmitri K DK

Scientific reports 20190411 1

Using all-atom explicit solvent replica exchange molecular dynamics simulations with solute tempering, we study the effect of methionine oxidation on Aβ10-40 peptide binding to the zwitterionic DMPC bilayer. By comparing oxidized and reduced peptides, we identified changes in the binding mechanism caused by this modification. First, Met35 oxidation unravels C-terminal helix in the bound peptides. Second, oxidation destabilizes intrapeptide interactions and expands bound peptides. We explain thes ...[more]

PMID: 30976055

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Project description:UnlabelledReactive chlorine species (RCS) defense mechanisms are important for bacterial fitness in diverse environments. In addition to the anthropogenic use of RCS in the form of bleach, these compounds are also produced naturally through photochemical reactions of natural organic matter and in vivo by the mammalian immune system in response to invading microorganisms. To gain insight into bacterial RCS defense mechanisms, we investigated Azospira suillum strain PS, which produces periplasmic RCS as an intermediate of perchlorate respiration. Our studies identified an RCS response involving an RCS stress-sensing sigma/anti-sigma factor system (SigF/NrsF), a soluble hypochlorite-scavenging methionine-rich periplasmic protein (MrpX), and a putative periplasmic methionine sulfoxide reductase (YedY1). We investigated the underlying mechanism by phenotypic characterization of appropriate gene deletions, chemogenomic profiling of barcoded transposon pools, transcriptome sequencing, and biochemical assessment of methionine oxidation. Our results demonstrated that SigF was specifically activated by RCS and initiated the transcription of a small regulon centering around yedY1 and mrpX. A yedY1 paralog (yedY2) was found to have a similar fitness to yedY1 despite not being regulated by SigF. Markerless deletions of yedY2 confirmed its synergy with the SigF regulon. MrpX was strongly induced and rapidly oxidized by RCS, especially hypochlorite. Our results suggest a mechanism involving hypochlorite scavenging by sacrificial oxidation of the MrpX in the periplasm. Reduced MrpX is regenerated by the YedY methionine sulfoxide reductase activity. The phylogenomic distribution of this system revealed conservation in several Proteobacteria of clinical importance, including uropathogenic Escherichia coli and Brucella spp., implying a putative role in immune response evasion in vivo.ImportanceBacteria are often stressed in the environment by reactive chlorine species (RCS) of either anthropogenic or natural origin, but little is known of the defense mechanisms they have evolved. Using a microorganism that generates RCS internally as part of its respiratory process allowed us to uncover a novel defense mechanism based on RCS scavenging by reductive reaction with a sacrificial methionine-rich peptide and redox recycling through a methionine sulfoxide reductase. This system is conserved in a broad diversity of organisms, including some of clinical importance, invoking a possible important role in innate immune system evasion.

Dataset Information

Methionine Oxidation Changes the Mechanism of A? Peptide Binding to the DMPC Bilayer.

Publications

Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer.

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