CHIRAL N-SUBSTITUTED GLYCINES CAN FORM STABLE HELICAL CONFORMATIONS

Background: Short sequence-specific heteropolymers of N-substituted gl ycines (peptoids) have emerged as promising tools for drug discovery. Recent work on medium-length peptoids containing chiral centers in the ir sidechains has demonstrated the existence of stable chiral conforma tions in solution. In this report, we explore the conformational prope rties of these N alpha chiral peptoids by molecular mechanics calculat ions and we propose a model for the solution conformation of an octame r of (S)-N-(1-phenylethyl)glycine. Results: Molecular mechanics calcul ations indicate that the presence of N-substituents in which the N alp ha carbons are chiral centers has a dramatic impact on the available b ackbone conformations. These results are supported by semi-empirical q uantum mechanical calculations and coincide qualitatively with simple steric considerations. They suggest that an octamer of (S)-N-(1-phenyl ethyl)glycine should form a right-handed helix with cis amide bonds, s imilar to the polyproline type I helix. This model is consistent with circular dichroism studies of these molecules. Conclusions: Peptoid ol igomers containing chiral centers in their sidechains present a new st ructural paradigm that has promising implications for the design of st ably folded molecules, We expect that their novel structure may provid e a scaffold to create heteropolymers with useful functionality.