Twists or turns: stabilising alpha beta turns in tetrapeptides.

Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (, + 3) hydrogen bonds and a beta/gamma (, ) or beta (, , ) turn; eight formed one (, + 4) hydrogen bond and twisted into a non-helical (, , , , ) or helical (, , ) alpha turn; one was less structured (). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a 1 (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (, , , , ) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.