Secondary structure inducing potential of beta-amino acids: Torsion angle clustering facilitates comparison and analysis of the conformation during MD trajectories

While numerous examples of P-peptides-exclusively composed of (beta-amino acids-have been investigated during the past decade, there are only few reports on the conformational preference of a single (beta-amino acid when incorporated into a cyclopeptide. The conformational bias of (beta-amino acids on the secondary structure of cyclopeptides has been investigated by NMR spectroscopy in combination with distance geometry (DG) and molecular dynamics (MD) calculations using experimental constraints. The atomic coordinate RMSD criterion usually employed for clustering of conformations after DG and MD calculations does not necessarily group similar peptide conformations, as there is an insufficient correlation between atomic coordinates and torsion angles. To improve on this shortcoming and to eliminate any arbitrary decisions during this process, a torsion angle clustering procedure has been implemented. For the cyclic pentapeptides cyclo-(-Val-(beta-Hala-Phe-Leu-Ile-) 1 and cyclo-(-Ser-Pro-Leu-(beta-Hasn-Asp-) 3, the (beta-amino acid is found in the central position of an extended y-turn (pseudo y-turn, psi gamma-turn), while the (beta-Hpro residue in the cyclic hexapeptide cyclo-(-Ser-(beta-HproLeu-Asn-Ile-Asp-) 5 preferentially occupies position i+1 of a pseudo P-turn (T(psi beta-turn). These results furthercorroborate the hypothesis of (beta-amino acids being reliable inducers of secondary structure in cyclic penta- and hexapeptides. They can be employed in the de novo design of biologically active cyclopeptides in pharmaceutical research, since the three-dimensional presentation of pharmacophoric groups in the side chains can be tailored by incorporation of (beta-amino acids in strategic sequential positions. (c) 2007 Wiley Periodicals, Inc.