Nucleation and stability of hydrogen-bond surrogate-based α-helices

We have reported a new class of artificial alpha-helices in which a pre-organized alpha-turn nucleates the helical conformation [R. N. Chapman, G. Dimartino, and P. S. Arora, J Am. Chem. Soc., 2004, 126, 12252 and D. Wang, K. Chen, J. L. Kulp, III, and P. S. Arora, J. Am. Chem. Soc., 2006, 128, 9248]. This manuscript describes the effect of the core nucleation template on the overall helicity of the peptides and demonstrates that the macrocycle which most closely mimics the 13-membered hydrogen-bonded alpha-turn in canonical alpha-helices also affords the most stable artificial alpha-helix. We also investigate the stability of these synthetic helices through classical helix-coil parameters and find that the denaturation behavior of HBS alpha-helices agrees with the theoretical properties of a peptide with a well-defined and stable helix nucleus.