Arginine-, d-arginine-vasopressin, and their inverso analogues in micellar and liposomic models of cell membrane: CD, NMR, and molecular dynamics studies

Abstract

We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [d-Arg8]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic–zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2–5 and 3–6 fragments. The inverso-analogues also adopt β-turns in the 3–6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr2, Phe3, and Arg8, important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr2 and Phe3 in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide–membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic–zwitterionic liposomes as well as the anionic–zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones.Electronic supplementary materialThe online version of this article (doi:10.1007/s00249-015-1071-4) contains supplementary material, which is available to authorized users.

Potent antidiuretic agonists, deamino‐vasopressin and desmopressin, and their inverso analogs: NMR structure and interactions with micellar and liposomic models of cell membrane

“…In summary, addition of the liposomes to the water differentiated the shapes of the CD spectra of vasopressin‐like peptides. Results of our recent studies confirmed the previously ones, that the smallest differences occurred with zwitterionic DPPC, the largest‐with anionic DPPG, and intermediate ones‐with mixed anionic‐zwitterionic liposomes. Moreover, upon increasing the negative charge at the liposomes surface, the intensity of 227‐nm band increases for both strong antidiuretic agonists, dAVP and dDAVP, especially for the more selective latter one.…”

“…In addition, with dAVP and dDAVP the 268‐nm band does not show two distinct shoulders in contrast to those in aqueous environment and the inverso analogs in lipid solution. In the long‐wavelength CD spectra of vasopressin‐like peptides, a slight inflection in the CD curve in water emerges around 250 nm, which completely disappears in the liposome solution . The same pattern has now been followed with both dAVP and dDAVP.…”

“… The differences between the amide proton chemical shifts of native vasopressin (AVP) and its analogs: dAVP (black), inverso ‐dAVP (gray), dDAVP (dark gray) and inverso ‐dDAVP (light gray), (Δδ NH = δ analog – δ AVP ). For AVP the values are taken from.…”

“…The complexes of the peptides with the mixed anionic‐zwitterionic micelles were obtained by their spontaneous formation during the first step of the MD simulations. We used the same procedure as reported previously …”

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

“…The starting coordinates of the DPC micelle-water system were taken from simulations conducted by Tieleman et al [36]. A single molecule of DPC was constructed on the basis of previously published parameters [37,38]. The pre-built hydrated DPC micelle consisted of 65 DPC monomers and 6305 water molecules.…”