BETA-VI TURNS IN PEPTIDES AND PROTEINS - A MODEL PEPTIDE MIMICRY

To investigate the role of proline in defining beta turn conformations within cyclic hexa- and pentapeptides we synthesized and determined the conformations of a series of L- and D-proline-containing peptides by means of 2D NMR spectroscopy and restrained molecular dynamics simulations. Due to cis/trans isomerism the L-proline peptides adopt at least two different conformations that are analyzed and compared to the structures of the corresponding D-proline peptides. The cis conformations of the compounds cyclo(-Pro-Ala-Ala-Pro-Ala-Ala-), cyclo(-Arg-Gly-Asp-Phe-Pro-Gly-), cyclo(-Arg-Gly-Asp-Phe-Pro-Ala-), cyclo (-Pro-Ala-Ala-Ala-Ala-), and cyclo(-Pro-Ala-Pro-Ala-Ala-) form uncommon betaVI turns that mimic the turn geometries found in crystallographically refined protein structures at such a detailed level that even preferred side chain orientations are reproduced. The ratios of the cis/trans isomers are analyzed in terms of the steric demand of the proline-following residue. The conformational details derived from this study illustrate the importance of the examination of small model compounds derived from protein loop regions, especially if bioactive recognition sequences, such as RGD (Arg-Gly-Asp), are incorporated.