Conformations of complex molecules such as cyclic peptides are tough to decipher. What a truism! I have mentioned this many times on this blog. Every now and then, I am forced to ask myself: how much effort do we really want to spend studying these complex systems? At times it feels as if we have a good grip on a given molecule, only to be disappointed by some capricious twist that throws all of our theories down the drain. The main reason things are difficult lies in the effects of media and additives, which can turn into the frustrating end of science. There are just so many geometrical variables a peptide of some complexity possesses that it is no surprise that things aren’t simple.
There are some monumental teachings from the past that suggest there is light at the end of the tunnel. Slowly but surely, I am compiling a list of additives with demonstrable ability to affect conformations as well as biological properties of cyclic peptides. One of these days I am going to publish a paper on this subject. For now, I just want to draw your attention to Dan Rich’s JACS paper from 1992 (the year I started graduate school, by the way). Cyclosporine A (shown below) is a known immunosuppressant that binds to cyclophilin (which is cyclosporine’s protein target). The trouble is, if the Leu-Leu amide bond in cyclosporine A is in its cis state, the molecule is biologically inactive. Dan Rich’s contribution demonstrates that the addition of LiCl to cyclosporine A in THF shifts the cis/trans equilibrium towards the bioactive trans form. What’s remarkable here is that the authors did not stop at evaluating the NMR spectra with and without LiCl, but convincingly demonstrated that the LiCl perturbation method works to alter the biological properties of cyclosporine A. According to the authors, a significantly more potent inhibition of cyclophilin is recorded in the presence of LiCl. Now – how about the effect of LiCl on the cellular permeability of cyclic peptides?