Oligoproline Helix Analyzed In Detail

Oligoprolines, short peptides made up only of the amino acid proline, form polyproline II (PPII) helices, the third-most-common peptide and protein secondary structure after α-helices and β-sheets. But no one has been able to structurally analyze PPII helices in detail because oligoprolines are difficult to crystallize.

Now, Helma Wennemers and coworkers at ETH Zurich have crystallized a modified oligo­proline and obtained the first high-resolution crystal structure of an oligoproline PPII helix (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja507405j). The oligoproline was modified with an N-terminal p-bromobenzoyl group.

“We had sheer luck, as is so often the case in crystallization, combined with the right touch by my student Patrick Wilhelm,” Wennemers says.

In addition to the key structural role they play in proteins such as collagen, oligoprolines have been used as molecular spacers and scaffolds for applications such as targeting tumors, forming nanoparticles, assembling supramolecular structures, and inhibiting protein-protein interactions. Dimensional and conformational information obtained from the new structure could help researchers design oligoprolines for specific applications.

In addition, the structure helps resolve long-standing controversies about the functional role of amide groups and water molecules in PPII helicity. The study revealed that neighboring amide groups in the helix interact and likely contribute to helix stability, whereas water is not present inside the crystal and is therefore not necessary for helicity.

Ron Raines of the University of Wisconsin, Madison, comments that the work is “a landmark advance in structural chemistry, providing the critical first look at the parent of the ubiquitous PPII structural motif in proteins.” The study’s accurate determination of the distance between prolines in the structure “will enable numerous studies in which oligoprolines are employed as molecular rulers,” Raines says.