| Affiliation: | (1) Department of Chemistry, D.G. Ruparel College, Senapati Bapat Marg, Mahim, 400 016 Mumbai, India;(2) Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, 400 098 Mumbai, India;(3) Tata Institute of Fundamental Research, Homi Bhabha Road Navy Nagar, Colaba, 400 005 Mumbai, India;(4) Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032-8202, USA |
| Abstract: | The conformation of a cyclic analog of neuropeptide Y [Tyr1--Lys--Gly--Arg--cyclo5/8-(Glu5--Tyr--Ile--Lys8)--Leu--Ile10--Thr--Arg--Pro--Arg--Tyr15--NH2; cEK-NPY] with high Y1 receptor affinity was studied using 1H, 13C and 15N 2D-NMR and CD in three diverse media-viz. DMSO-d6, water (pH 4.0) and 50% hexafluoroacetone (HFA). The conformation of cEK-NPY was interpreted based on chemical shift (1H, 13C and 15N), temperature coefficients of the NH chemical shifts, 3JNHα coupling constants and the pattern of intra and inter-residue NOE’s and the CD spectrum. In both DMSO and water, there is a preponderance of a β-strand structure, while HFA promotes an α-helical structure, which is discontinuous in the mid-region of the peptide, due to the constraints of the lactam ring. The solution structures were generated using Restrained Molecular Dynamics simulations and further refined by Mardigras to R factors between 0.55 and 0.65. The role of its conformations in its biological activity is discussed. |
