The cisproline(i-1)-aromatic(i) interaction: Folding of the Ala-cisPro-Tyrpeptide characterized by NMR and theoretical approaches

Cisproline(i-1)-aromatic(i) interactions have been detected in several shor t peptides in aqueous solution by analysis of anomalous chemical shifts mea sured by H-1-NMR spectroscopy. This formation of local structure is of impo rtance for protein folding and binding properties. To obtain an atomic-deta il characterisation of the cisproline(i-1)-aromatic(i) interaction in terms of structure, energetics and dynamics, we studied the minimal peptide unit , blocked Ala-cisPro-Tyr, using computational and experimental techniques. Structural database analyses and a systematic search revealed two groups of conformations displaying a cisproline(i-1)-aromatic(i) interaction. These conformations were taken as seeds for molecular dynamics simulations in exp licit solvent at 278 K. During a total of 33.6 ns of simulation, all the 'f olded' conformations and some 'unfolded' states were sampled. H-1- and C-13 -chemical shifts and (3)J-coupling constants were measured for the Ala-Pro- Tyr peptide. Excellent agreement was found between all the measured and com puted NMR properties, showing the good quality of the force field. We find that under the experimental and simulation conditions, the Ala-cisPro-Tyr p eptide is folded 90% of the time and displays two types of folded conformat ion which we denote 'a' and 'b'. The type a conformations are twice as popu lated as the type b conformations. The former have the tyrosine ring intera cting with the alanine alpha proton and are enthalpically stabilised. The l atter have the aromatic ring interacting with the proline side chain and ar e entropically stabilised. The combined and complementary use of computatio nal and experimental techniques permitted derivation of a detailed scenario of the 'folding' of this peptide.