Vol.:(0123456789) 1 3 European Biophysics Journal (2019) 48:25–34 https://doi.org/10.1007/s00249-018-1327-x ORIGINAL ARTICLE Efect of triphenylphosphonium moiety on spatial structure and biointeractions of stereochemical variants of YRFK motif Ruslan Garifullin 1  · Dmitriy S. Blokhin 1,2  · Rezeda A. Akhmadishina 1  · Natalia V. Petrova 1  · Alexandra M. Kusova 1,3  · Vladimir V. Klochkov 2  · Timur I. Abdullin 1 Received: 22 May 2018 / Revised: 24 July 2018 / Accepted: 6 August 2018 / Published online: 13 August 2018 © European Biophysical Societies’ Association 2018 Abstract Chemical modifcation of therapeutic peptides is an important approach to improving their physicochemical and pharmacoki- netic properties. The triphenylphosphonium (TPP) cation has proved to be a powerful modifer; however, its efects on peptide structure and activity remain uncharacterized. In this study, cytoprotective tetrapeptides based on the YRFK opioid motif with L- or D-Arg residues were linked to (triphenylphosphonio)carboxylic acids with ethylene and pentylene spacers (TPP-3 and TPP-6 groups, respectively). The three-dimensional structure of the oligopeptides was analyzed by NMR spectroscopy, computational methods and circular dichroism (CD). A more compact and bent structure with segregated aromatic groups was revealed for the D-arginine-containing tetrapeptide and its TPP-6 derivative. The TPP moiety caused structure-organizing efect on the tetrapeptides, resulting in transition from random coil to β-sheet structures, and decreased the peptide backbone fexibility up to ten times. The TPP-3-modifed oligopeptide with the lowest RMSD value (ca. 0.05 Å) was characterized by intrapeptide hydrophobic interactions between the TPP and side groups of Tyr and Phe residues accompanied by strong CD induction. The TPP-6-modifed oligopeptides showed enhanced ability to form intermolecular associates and disturb liposomal membranes. The relationship between the spatial structure of the oligopeptides and some of their biologically relevant interactions were additionally revealed and are discussed. Keywords Cationic–aromatic oligopeptides · YRFK motif · Triphenylphosphonium derivatives · NMR spectroscopy · Three-dimensional structure · Biointeractions Introduction Oligopeptides are an important object of biomedical research. They are being intensively investigated as bioactive molecules, drug candidates and protein models (Fosgerau and Hofmann 2015; Shiba 2010; Vlieghe et al. 2010). Oli- gopeptides are characterized by a potentially high activity and specifcity, which could be observed for the simplest di- and tripeptide motifs (Andrea et al. 2005; Ung and Winkler 2011). However, most bioactive peptides are characterized by rapid enzymatic degradation and low cellular and tis- sue availability which restrict their biomedical application (Shiba 2010). Chemical conjugation of oligopeptides with artifcial compounds, including amino acid analogues, is an estab- lished way of increasing stability and improving pharma- cokinetic properties of oligopeptides without substantial disruption of their natural structure and functions. For this purpose, terminal and/or side group modifcation of peptides Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00249-018-1327-x) contains supplementary material, which is available to authorized users. * Dmitriy S. Blokhin dblohin@kpfu.ru * Timur I. Abdullin tabdulli@gmail.com; timur.abdullin@kpfu.ru 1 Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan 420021, Russia 2 Institute of Physics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., Kazan 420008, Russia 3 Kazan Institute of Biochemistry and Biophysics FSBIS KSC RAS, 2/31 Lobachevsky St., Kazan 420111, Russia