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

Abstract

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 = (-)O(2)C-(CH(2))(n)-CO, 0 < or = n < or = 3, are superior to N-acetyl, as are N-acylglycyl and N-acyl-beta-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.

N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes

“…We and others have shown that the primary consequence of N-terminal acetylation in the free state of aSyn is to increase the helicity of the N-terminal ϳ10 residues (30,32,33), an effect that likely results from the known ability of an N-acetyl group to act as a helix cap (71,72), which would stabilize the transiently helical structure formed at the N terminus. We (35,39) and others (33,73) have postulated that transient helical character at the very N-terminal region may be important in a The population of all bound states was calculated as the ratio of the average intensity ratio of residues 3-9, which are expected to be bound in both fully and partly helical binding modes, to the average intensity ratio of residues 129 -137, which remain unbound even at high lipid concentrations, subtracted from 1. b The population of the extended helix state was calculated as the ratio of the average intensity ratio of residues 65-80, which are in the second half of the lipid binding domain and have well resolved HSQC peaks, to the average intensity ratio of residues 129 -137, subtracted from 1. c Apparent dissociation constants were derived from fitting the bound populations of each state at several lipid concentrations to Equation 2, derived from a simple bimolecular binding equilibrium.…”

Helix‐coil energetics for helix formers and breakers reflect context and temperature: Mutants of helically robust, guest‐sensitive homopeptide hosts

“…Studies using these host-guest mutants addressed the energetic effects of variations in sequence length; residue composition; local hydrophobic, polar, and charged contacts between residue side chains; end-cap structure; and charges near helical termini dipoles. [1][2][3] For practical reasons, nearly all peptide studies during this period relied on data collected at low temperatures. Two major motivations drive this project.…”

17 The protein epitope mimetic approach to protein-protein interaction inhibitors

“…Some of the approaches used so far to stabilize helical conformations in peptides include the use of intramolecular hydrogen-bond surrogates , such as hydrazone or alkenyl links (Cabezas and Satterthwait 1999;Chapman et al 2004;Henchey et al 2010;Patgiri et al 2008;Vernall et al 2009;Wang et al 2005Wang et al , 2006Wang et al , 2008, and helical end-capping groups (Figure 17.3) (Austin et al 1997;Curran 1988a, 1988b; Kemp et al , 1996Lewis et al 1998;Maison et al 2001;Obrecht et al 1999;Schneider and DeGrado 1998). Other methods to enhance helicity in peptides include incorporating unnatural amino acids (Andrews and Tabor 1999), in particular, α-disubstituted amino acids such as Aib (Venkatraman et al 2001) and other α-alkylated-α-amino acids.…”