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

Abstract

We have reported a new class of artificial α-helices in which a pre-organized α-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 α-turn in canonical α-helices also affords the most stable artificial α-helix. We also investigate the stability of these synthetic helices through classical helix-coil parameters and find that the denaturation behavior of HBS α-helices agrees with the theoretical properties of a peptide with a well-defined and stable helix nucleus.

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

“…For testing helical propensity, we employed the hydrogen bond surrogate peptide (HBSP) of Arora and colleagues 36, 55 . With a covalently pre-organized nucleus that avoids the limiting entropic cost of helix initiation, experiments indicate the presence of significant helical content despite the short length of only 10 amino acids, providing an ideal initial model system.…”

Synthesis of Hydrogen‐Bond Surrogate α‐Helices as Inhibitors of Protein‐Protein Interactions

“…This constraint forces N-terminal helix nucleation and allows for helix formation to occur more readily in short peptides. Improvement of α-helical character for HBS compounds over linear peptides has been reproducibly shown using circular dichroism spectroscopy (Figure 1B) (Chapman et al, 2004; Henchey et al, 2010a; Henchey et al, 2010b; Wang et al, 2006a; Wang et al, 2006b; Wang et al, 2005; Wang et al, 2008). Further structural analyses by 2D NMR spectroscopy and X-ray crystallography (Figure 1C) confirm the helical conformation adopted by HBS compounds (Liu et al, 2008; Patgiri et al, 2012; Wang et al, 2006b).…”

A 310-helix single turn enforced by crosslinking of lysines with 1,1′-ferrocenedicarboxylic acid

“…As noted by many researchers, including Kemp [12,13], Bartlett [14], and Arora [20], a signature of helices is the observation of NOEs between consecutive amide NH protons [d NN (i, i+1)]. The amide NH region portion of the ROESY spectrum of 1 is shown in Fig.…”

“…Linking the side chains forces the internal portion of the peptide to be helical; those parts of the peptide adjacent to the constraint are then positioned to propagate the helix. In a third approach, the constraint can be made by replacing the intramolecular hydrogen bond with a covalent spacer [5,20]. As with the other approaches, this constraint enforces a helical conformation on a small part of the peptide; amino acid residues outside the constraint are then positioned to extend the helix.…”