Optimal N-Caps for N-Terminal Helical Templates:  Effects of Changes in H-Bonding Efficiency and Charge

• Published in: Journal of the American Chemical Society Vol. 123; no. 42; pp. 10245 - 10254
• Main Authors: Maison, Wolfgang, Arce, Eva, Renold, Peter, Kennedy, Robert J, Kemp, Daniel S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.2001; Amer Chemical Soc
• Subjects: Amides - chemistry; Chemistry; Chemistry, Multidisciplinary; Circular Dichroism; Dipeptides - chemistry; Hydrogen Bonding; Nuclear Magnetic Resonance, Biomolecular; Peptides - chemistry; Physical Sciences; Protein Conformation; Protein Structure, Secondary; Science & Technology; Templates, Genetic; AMINO-ACIDS; SIDE-CHAIN; STABILIZATION; BETA-SHEET FORMATION; SHORT PEPTIDES; ENERGETICS; CONFORMATIONAL-ANALYSIS; PROTEINS; ALPHA-HELICES; AQUEOUS-SOLUTION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja010812a

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. Am. 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-formyl cap is found to be equivalent to the N-acetyl and may provide more convenient quantitative helix reporting properties. Anionic N-caps derived from the series X = -O2C-(CH2) n -CO, 0 ≤ n ≤ 3, are superior to N-acetyl, as are N-acylglycyl and N-acyl-β-aspartyl. The latter pair of caps permit introduction of the X-Hel functionality within a polypeptide chain, allowing control of helicity of a peptide sub-sequence. Applications of these capping functions are discussed. This work has been focused primarily on immediate practical goals directed toward enhancing the maximum helicity of isolated short to medium-sized peptides in aqueous solution, but its developing concepts and working hypotheses are likely to significantly enhance our understanding at a chemical level of the protein folding problem.