Helical Mimetics protein

Fig. 10a implies that shared (bifurcated) hydrogen bonds dominate the statistical picture of helical conformation in proteins and must be considered in helical mimetic design. 

Complexes that feature a-helices at interfaces were studied because a-helices constitute the largest class of protein secondary structure and mediate many protein interactions [30, 51]. Helices located within the protein core are vital for the overall stability of protein tertiary structure, whereas exposed a-helices on protein surfaces constitute central bioactive regions for the recognition of numerous proteins, DNAs, and RNAs. Importantly, helix mimetics have emerged as a highly effective class of PPI inhibitors [32, 36, 44, 52-55]. 

Although biologically active helical y-peptides have not been reported so far, the striking structural similarities (polarity and helicity) between the a-helix of L-a-peptides and the (P)-2.6i4-hehx of y-peptides suggest that the 2.614-helical backbone might prove useful as a template for elaborating functional mimetics of a-helical surfaces and intervening in protein-protein interactions. 

Protein helices generally adopt variations of the usual helix geometries depending on the environment. 1 The methods described in Sections 12.3.1 and 12.3.2 will refer only to the synthesis of peptides incorporating inducers and mimetics for the a- and 310-helices. 

In this section, the composition and characteristics of helical domains identified to be critical for protein complex formation is discussed. This analysis allows prediction of the type of helix mimetic that is best suited for the type of helical interface. 

A study by Bullock et al. revealed that roughly 60% of helical interfaces in the HIPP dataset feature helices with hot spot residues on one face of the helix (Fig. 6b, d), a third of the complexes utilize helices with hot spots on two faces (Fig. 6b, e), and roughly 10% require all three faces for interaction with the target protein partner (Fig. 6b, f). The full list of PPIs that correspond to each category is published elsewhere [67]. Overall percent occurrences of hot spot residues at the first 12 positions in interfacial helices are depicted in Fig. 6c. The results of the study indicate that helix surface mimetics may prove to be a highly effective class of synthetic... 

Fig. 7 Potential of various helix mimetics to reproduce functionality of one, two, or all three faces of protein a-helices (Reprinted with permission from Bullock et al. [67], Copyright (2011) American Chemical Society)...

Fig. 13 Stabilized helices and nonnatural helix mimetics several strategies that stabilize the a-helical conformation in peptides or mimic this domain with nonnatural scaffolds have been described. Recent advances include [1-peptide helices, terphenyl helix-mimetics, mini-proteins, peptoid helices, side-chain crosslinked a-helices, and the hydrogen bond surrogate (HBS) derived a-helices. Circles represent amino acid side-chain functionality (Reprinted from Henchey et al. [52], Copyright (2008) with permission from Elsevier)...

Similar to p-sheet, a-helix has also been extensively studied for self-assembly and used for fabricating self-assembled nanostructures. In a general strategy, peptides bio-mimetically mimicking the helices in natural proteins are synthesized first, and a-hehx formed by these peptides can further self-assemble into higher-order structures with, for example, a coiled coil conformation [6], Due to space limitations, readers can refer to other sources for more information about a-helix (references [3,6], etc.). 

---