Anion complexes of small Boc-protected lysine cyclopeptides in solution

Anion binding affinities of tetra-, penta-, and hexahomocyclopeptides comprised of lysine subunits with Boc protected side chains were studied in acetonitrile and dimethyl sulfoxide. The anions included were chloride, bromide, iodide, nitrate, thiocyanate, hydrogen sulfate, and dihydrogen phosphate. Complexation reactions were monitored by ITC and NMR titrations, whereas the structural characteristics of experimentally observed complexes were determined by classical and/or QM/MM molecular dynamics simulations. The results clearly indicated that the studied receptors bound the anions with moderate to high affinity, forming species of 1:1 stoichiometry and in some instances anion sandwich complexes. In the case of dihydrogen phosphate binding, formation of complexes with anion dimer or trimer was also observed. The ring size had a strong effect on the cyclopeptide anion affinity, whereby tetra- and pentameric compounds formed more stable complexes with almost all anions than the hexameric one. This could be related to the differences in intramolecular hydrogen bonding in the free receptors and with the geometry of the binding site. The findings presented indicate that the four- and five-membered cyclopeptides are suitable for the design of high-affinity anion receptors in organic solvents, whereas the six-membered rings could be used for selective dihydrogen phosphate binding.