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 N alpha 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 N alpha 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-(1-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 dichorism 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.

A surface of minimum area metric for the structural comparison of proteins.

A new method for comparing protein structures, based on a minimal surface metric, is developed. A virtual polypeptide backbone is created by joining consecutive C alpha atoms in a protein structure. The minimal surface between the virtual backbones of two proteins (the Area Functional) is determined numerically using an iterative triangulation strategy. The first protein is then rotated and translated in space until the smallest minimal surface is obtained. Such a technique yields the optimal structural superposition between two protein segments. It requires no initial sequence alignment, is relatively insensitive to insertions and deletions, and obviates the need to select a gap penalty. The optimal minimal area can then be converted to the Area-C alpha distance, measured in angstroms, to determine the structural similarity. This technique has been applied to a large class of proteins and is able to detect not only small-scale differences between closely related proteins but also large-scale topological similarities between evolutionary unrelated proteins that lack any obvious sequence homology. To measure the similarity between structurally dissimilar proteins, an additional measure (the Fit Comparison) is developed. This is a scale-invariant measure of a structural similarity that is useful for determining topological similarities between dissimilar proteins with unrelated sequences.