THE SOLUTION CONFORMATION OF AC-PEN-ARG-GLY-ASP-CYS-OH, A POTENT FIBRINOGEN RECEPTOR ANTAGONIST

The solution conformation of Ac-Pen-Arg-Gly-Asp-Cys-OH, a potent fibri nogen receptor antagonist, was characterized in DMSO-d6 by the combina tion of nmr and molecular modeling. The conformational space available to the peptide was explored using a distance geometry algorithm with distance constraints derived from H-1-nmr spectra. The dynamics of the peptide were examined by relaxation time measurements and low tempera ture studies. The results from the low temperature studies suggest tha t the peptide backbone does not exist in a single, well-defined confor mation but undergoes exchange between multiple conformers. This result is consistent with the inability to find a single structure that sati sfies all the nmr-derived constraints. The constraints could only be s atisfied by considering pairs of conformers to represent the experimen tal data. The low energy conformers comprise type II' or type V beta-t urns with distinct side-chain directionality. The Arg-Gly-Asp portion of the ring is flexible and can be described by amide-plane rotations of the Arg-Gly and Gly-Asp peptide bonds. Although some backbone flexi bility is evident, the incorporation of beta,beta-dimethyl cysteine im parted greater conformational rigidity as compared to the previously s tudied cyclic pentapeptide, Ac-Cys-Arg-Gly-Asp-Cys-OH. (C) 1993 John W iley & Sons, Inc.