Conformational Preferences of RNase A C-Peptide Derivatives Containing a Highly Constrained Analogue of Phenylalanine
journal contributionposted on 02.09.1998, 00:00 by Destardi Moye-Sherman, Song Jin, Inhye Ham, Dongyeol Lim, J. Martin Scholtz, Kevin Burgess
Both enantiomers of a highly constrained derivative of phenylalanine, FiFi, were prepared in optically pure form. Studies were performed to elucidate the effects of substituting this amino acid for phenylalanine in RN-24, a derivative of the RNase A C-peptide. Thus RN-24, and the analogues 9 and 10, in which Phe-8 was replaced by each of the enantiomers of FiFi, were prepared. Comparative circular dichroism (CD) experiments indicated relative tendencies to adopt helical structures, and variable-temperature CD studies showed the relative ease with which these conformations were lost at elevated temperatures. These observations were rationalized via computer-assisted molecular modeling, which showed that the phenyl groups of (R,R)-FiFi in the peptidomimetic 9 can be accommodated via distortion of the helical conformations and that such distorted conformations persist as the temperature is increased. Conversely, intolerable contacts occur in an analogous conformation of the (S,S)-FiFi peptidomimetic 10 and these preclude helicity. Consistent with these observations, molecular dynamics studies of these peptidomimetics at 276 K indicate that helical conformations of 9 and RN-24 are observable under conditions in which the analogous conformation of 10 is lost. Overall, these studies demonstrate that cyclopropane amino acids can be used to enforce elements of secondary structure (albeit distorted) or to preclude them altogether.