Optimal N-caps for N-terminal helical templates: Effects of changes in H-bonding efficiency and charge

A family of efficient helix-initiating N-terminal caps X-Hel is introduced that expand the scope and versatility of the previously reported reporting conformational template Ac-Hel, (Kemp, D. S.; Allen, T. J.; Oslick, S. J. A m. Chem. Soc. 1995, 117, 6641-6657) and a working principle for predicting cap performance is described, based on structurally specific intramolecular hydrogen bond formation. Replacement of the N-acetyl by urethane, urea, or sulfonamide generated less efficient polypeptide helix inducers. The N-for myl cap is found to be equivalent to the N-acetyl and may provide more conv enient quantitative helix reporting properties. Anionic N-caps derived from the series X = -O2C-(CH2)(n)-CO, 0 less than or equal to n < 3, are superi or to N-acetyl, as are N-acylglycyl and N-acyl-beta -aspartyl. The latter p air of caps permit introduction of the X-Hel functionality within a polypep tide chain, allowing control of helicity of a peptide sub-sequence. Applica tions of these capping functions are discussed. This work has been focused primarily on immediate practical goals directed toward enhancing the maximu m helicity of isolated short to medium-sized peptides in aqueous solution, but its developing concepts and working hypotheses are likely to significan tly enhance our understanding at a chemical level of the protein folding pr oblem.