TY - JOUR
T1 - Conformation of Cyclic Analogs of Substance P
T2 - NMR and Molecular Dynamics in Dimethyl Sulfoxide
AU - Saulitis, Juris
AU - Mierke, Dale F.
AU - Byk, Gerardo
AU - Gilon, Chaim
AU - Kessler, Horst
PY - 1992/6/1
Y1 - 1992/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0026751476&partnerID=8YFLogxK
U2 - 10.1021/ja00038a054
DO - 10.1021/ja00038a054
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AN - SCOPUS:0026751476
SN - 0002-7863
VL - 114
SP - 4818
EP - 4827
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 12
ER -