title: The importance of N-methylations for the stability of the β⁶·³-helical conformation of polytheonamide B.
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 [Formula: see text]-helical conformation. Unusually, the wide [Formula: see text]-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 [Formula: see text]-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 [Formula: see text]-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.
authors.affiliation: Laboratory of Physical Chemistry, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Renevey
authors.affiliation: Laboratory of Physical Chemistry, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland. sriniker@ethz.ch.
authors.forename: Sereina
authors.initials: S
authors.lastname: Riniker
mesh_terms: D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D056004:Molecular Dynamics Simulation; D009584:Nitrogen / Q000737:chemistry* / Q000378:metabolism*; D000072756:Protein Conformation, alpha-Helical; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C111717:polytheonamide B; D009584:Nitrogen
keywords: Beta-helices; Molecular dynamics; Posttranslational modifications; RiPPs