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.