title: Oxidation increases the strength of the methionine-aromatic interaction.
abstract: Oxidation of methionine disrupts the structure and function of a range of proteins, but little is understood about the chemistry that underlies these perturbations. Using quantum mechanical calculations, we found that oxidation increased the strength of the methionine-aromatic interaction motif, a driving force for protein folding and protein-protein interaction, by 0.5-1.4 kcal/mol. We found that non-hydrogen-bonded interactions between dimethyl sulfoxide (a methionine analog) and aromatic groups were enriched in both the Protein Data Bank and Cambridge Structural Database. Thermal denaturation and NMR spectroscopy experiments on model peptides demonstrated that oxidation of methionine stabilized the interaction by 0.5-0.6 kcal/mol. We confirmed the biological relevance of these findings through a combination of cell biology, electron paramagnetic resonance spectroscopy and molecular dynamics simulations on (i) calmodulin structure and dynamics, and (ii) lymphotoxin-α binding toTNFR1. Thus, the methionine-aromatic motif was a determinant of protein structural and functional sensitivity to oxidative stress.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Lewis
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Dunleavy
authors.affiliation: Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Senkow
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Her
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Horn
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jersett
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Mahling
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: McCarthy
authors.affiliation: Department of Chemistry, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Gabriella T
authors.initials: GT
authors.lastname: Perell
authors.affiliation: Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Valley
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Karim
authors.affiliation: Department of Chemistry, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Jiali
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Chemistry, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: William C K
authors.initials: WC
authors.lastname: Pomerantz
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cembran
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota-Duluth, Duluth, Minnesota, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Hinderliter
authors.affiliation: Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
mesh_terms: D006841:Hydrocarbons, Aromatic / Q000737:chemistry* / Q000378:metabolism; D008715:Methionine / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011789:Quantum Theory
chemical_list: D006841:Hydrocarbons, Aromatic; D008715:Methionine