Oxidation increases the strength of the methionine-aromatic interaction

Andrew K. Lewis, Katie M. Dunleavy, Tiffany L. Senkow, Cheng Her, Benjamin T. Horn, Mark A. Jersett, Ryan Mahling, Megan R. McCarthy, Gabriella T. Perell, Christopher C. Valley, Christine B. Karim, Jiali Gao, William C.K. Pomerantz, David D. Thomas, Alessandro Cembran, Anne Hinderliter, Jonathan N. Sachs

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28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)860-866
Number of pages7
JournalNature Chemical Biology
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2016

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    Lewis, A. K., Dunleavy, K. M., Senkow, T. L., Her, C., Horn, B. T., Jersett, M. A., Mahling, R., McCarthy, M. R., Perell, G. T., Valley, C. C., Karim, C. B., Gao, J., Pomerantz, W. C. K., Thomas, D. D., Cembran, A., Hinderliter, A., & Sachs, J. N. (2016). Oxidation increases the strength of the methionine-aromatic interaction. Nature Chemical Biology, 12(10), 860-866. https://doi.org/10.1038/nchembio.2159