Chiral N-substituted glycines can form stable helical conformations

Background:

Short sequence-specific heteropolymers of N-substituted glycines (peptoids) have emerged as promising tools for drug discovery. Recent work on medium-length peptoids containing chiral centers in their sidechains has demonstrated the existence of stable chiral conformations in solution. In this report, we explore the conformational properties of these Nα chiral peptoids by molecular mechanics calculations and we propose a model for the solution conformation of an octamer of (S)-N-(1-phenylethyl)glycine.

Results:

Molecular mechanics calculations indicate that the presence of N-substituents in which the Nα carbons are chiral centers has a dramatic impact on the available backbone conformations. These results are supported by semi-empirical quantum mechanical calculations and coincide qualitatively with simple steric considerations. They suggest that an octamer of (S)-N-(phenylethyl)glycine should form a right-handed helix with cis amide bonds, similar to the polyproline type I helix. This model is consistent with circular dichroism studies of these molecules.

Conclusions:

Peptoid oligomers containing chiral centers in their sidechains present a new structural paradigm that has promising implications for the design of stably folded molecules. We expect that their novel structure may provide a scaffold to create heteropolymers with useful functionality.