A fascinating study was recently reported by Hunter and colleagues in Angewandte Chemie. First of all, here is a bit of history. If you follow the classic work of Horst Kessler, you know that there is evidence-based model that suggests that the conformational preferences of a given cyclic peptide are dictated by the composition of its structural core elements. In other words, if you want to make a difference to a given molecule, side chains are unlikely to be of much use, unless, of course, you make bicycles, stapled peptides, and so on. But short of making drastic differences along these lines, what has really works well are changes in the absolute stereochemistry of the core residues. This way, one can really get profound structural changes.
The reason I enjoyed reading the Hunter paper is that it documents the effect of fluorine atoms (recall that famous guache effect) on the solution conformation of cyclic peptides. The authors used the natural product unguisin A as a model. The fluorine effect here can be traced back to what happens with dipoles in vicinal difluorides. The NMR analysis of NH chemical shifts (and a range of other parameters) led the authors to the conclude that the diastereomeric macrocycles shown below are drastically different in their conformation. You can see this in the patterns of intramolecular hydrogen bonds that I have indicated. This is a new strategy to change conformations of cyclic peptides. While I fully understand the challenges that are likely to arise if one intends to put this to wider practice (it is still not trivial to site-selectively introduce a fluorine atom into an organic molecule), this work is fabulous.