Conformation of Cyclic Analogs of Substance P: NMR and Molecular Dynamics in Dimethyl Sulfoxide

Juris Saulitis, Dale F. Mierke, Gerardo Byk, Chaim Gilon, Horst Kessler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The conformational analysis of two cyclic analogues of substance P has been carried out using NMR spectroscopy and restrained molecular dynamics calculations. The cyclic analogues, cyclo[-(CH2)m-NH-CO-(CH2)n-CO-Arg-Phe-Phe- N-]-CH2-CO-Leu-Met-NH2 (with m, n = 3, 2 and 3, 3), show a large percentage of cis configurational isomers (18 and 22%) about the substituted amide. The additional isomers lead to severe spectral overlap of the proton resonances. Using the carbon resonances and the associated large chemical shift dispersion allows for the unambiguous assignment of all proton resonances. From the NOEs, temperature gradients, and coupling constants the conformation of the cyclic portion of the molecule is well-determined. The structures obtained from the experimental study were refined with NOE-restrained molecular dynamics. The computer simulations were carried out in dimethyl sulfoxide, the same solvent used in the experimental study. The dynamic stability of the refined conformations was evaluated by performing an extended, free MD simulation (400 ps) in dimethyl sulfoxide. The comparison of the interproton distances from the NOEs (two-spin approximation) with the effective distances from the free MD simulation is introduced as a possible tool to test the quality of obtained structures.

Original languageEnglish
Pages (from-to)4818-4827
Number of pages10
JournalJournal of the American Chemical Society
Volume114
Issue number12
DOIs
StatePublished - 1 Jun 1992

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