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The importance of N-methylations for the stability of the \(\beta ^{6.3}\)-helical conformation of polytheonamide B

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Abstract

Polytheonamide B (pTB), a highly cytotoxic peptide produced by a symbiotic bacterium of the marine sponge Theonella swinhoei, forms a transmembrane pore consisting of 49 residues. More than half of its residues are posttranslationally modified. Epimerizations result in alternating L- and D-amino acids that allow the peptide to adopt a \(\beta ^{6.3}\)-helical conformation. Unusually, the wide \(\beta ^{6.3}\)-helix of pTB is stable in a polar environment, which is in contrast to gramicidin A, an antibiotic with similar function and structure. The role of the other posttranslational modifications (PTMs) such as side chain hydroxylations, C- and N-methylations is not well understood. In this study, the importance of these PTMs for the stability of \(\beta ^{6.3}\)-helix is investigated using computational tools. By reverting the modified residues to their precursors and monitoring the effect on the dominant structure, we show that the N-methylations are crucial for the stability of the \(\beta ^{6.3}\)-helix in a polar environment. They are the driving force for the formation of stable side chain hydrogen-bond chains that act as an “exoskeleton.” Such exoskeletons could present a general design strategy for helical peptides.

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Acknowledgments

The authors thank Michael Freeman and Jörn Piel for useful discussions. A. R. thanks Victor Holanda Rusu and Jožica Dolenc for help with the analysis. The authors gratefully acknowledge financial support by the Swiss National Science Foundation (Grant Number 200021-159713) and by ETH Zürich (ETH-08 15-1).

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  1. Laboratory of Physical Chemistry, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland

    Annick Renevey & Sereina Riniker

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  1. Annick Renevey
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  2. Sereina Riniker
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Correspondence to Sereina Riniker.

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Renevey, A., Riniker, S. The importance of N-methylations for the stability of the \(\beta ^{6.3}\)-helical conformation of polytheonamide B. Eur Biophys J 46, 363–374 (2017). https://doi.org/10.1007/s00249-016-1179-1

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  • DOI: https://doi.org/10.1007/s00249-016-1179-1

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