Structure and dynamics of synthetic O-glycosylated cyclopeptide in solution determined by NMR spectroscopy and MD calculations (original) (raw)

1992, Journal of the American Chemical Society

Conformational analysis by NMR spectroscopy and restrained molecular dynamics (MD) of the 0-glycosylated cyclic hexapeptide cyclo(~-Prol-Phe~-Ala'-Ser~[ 0-2-deoxy-~-lactopyranosyl-a-( 1-3)]-Phe5-Phe6) (I) and the cyclic hexapeptide precursor cyclo(~-Pro'-Phe~-Ala~-Ser~-Phe~-Phe~) (11) is described. For II, an X-ray structure was obtained and compared with the structure in solution. For both compounds, the distance constraints derived from 2D NMR measurements could not be completely satisfied by a single conformation, but distance violations occurred only in the PheS region of the peptide. The specific pattern of NOE-derived distances in this part of the molecule suggested an equilibrium between two conformers containing 01and BII-type turns, respectively, with PheS at i + 2. MD simulations with time-dependent distance constraints support the assumption of a bI/BII flip in I and 11. The conformations were refined using restrained MD simulations in vacuo, in water, and in DMSO. To study the exoanomeric effect of b(1-4)-and a-glycosidic linkages on conformation, new force field parameters derived from literature data were incorporated, leading to greater flexibility and significantly populated alternate conformers around the b( 1-4)-glycosidic bond, in agreement with literature data. The a-glycosidic linkage connecting the disaccharide moiety to the peptide prefers only one conformation. Both I and I1 have similar backbone conformations and hydrogen-bonding patterns. Therefore, the 0-glycosylation does not affect the conformation or the overall shape of the peptide backbone or side chains. ~ ~~ ~~~ (1) (a) Feizi, T. Nature 1985, 314, 53-57. (b) Feizi, T.; Childs, R. A.