Helix breakers

The tendencies of the amino acids to stabilize or destabilize a-helices are different in typical proteins than in polyamino acids. The occurrence of the common amino acids in helices is summarized in Table 6.1. Notably, proline (and hydroxyproline) act as helix breakers due to their unique structure, which fixes the value of the —N—C bond angle. Helices can be formed from either... 

After Ala, residues with long side chains exhibit higher tendencies to form helices due to possible position-dependent, side-chain interactions that are helix stabilizing, such as salt bridges and hydrogen bonding. However, aromatic or ((-branched side chains act as helix breakers in monomeric peptides due to constraints on side-chain rotational entropy when in an a-helical conformation/11,14 201... 

Gly is another helix breaker and is often found at the C-terminus of a helix. The lack of a side chain in the a-carbon of Gly not only deprives it of helix-promoting side-chain interactions, but also increases its backbone conformational flexibility, favoring a random coil conformation. 

Aim to characterize amino acids and templates as Helix Former <== Helix Compatible ==> Helix Breaker... 

In the case of proline, the amide group is part of a five-membered ring and rotation about the C-N bond is not possible. Therefore, proline is considered a helix breaker and is rarely found in helices. If proline is found in an a helix, a bend or kink in the helix is usually observed at that point. Alanine, glutamic acid, leucine, and methionine are good helix formers, while proline, glycine, tyrosine, and serine are not. 

Based on the findings from an alanine scan, further peptides can be synthesized in which residues involved in the receptor recognition are substituted by homologous amino acids. Interesting in this context is also the use of conformation-ally constrained analogues in which amino acid residues such as the helix breaker proline or the tum-inducing motive alanine-aminoisobutyric acid are introduced into the natural peptide sequence. 

In the right-handed a-helix, the peptide chain forms a helix (like a cork screw) with the side groups on the outside, where each turn takes 3.6 residues (18 residues making 5 turns) the translation of the helix is 0.15 nm per residue (i.e., a pitch of 0.54 nm per turn), compared to 0.36 nm per residue for a stretched chain (Figure 7.2). The helical conformation is stabilized by H-bonds, between the O of peptide bond i and the NH of peptide bond i + 4. Moreover, enhanced van der Waals attraction is involved. The possibility for the latter to occur varies among amino acid residues, which means that not all of them readily partake in an a-helix. Ala, Glu, Phe, His, lie, Leu, Met, Gin, Val, and Trp have strong tendencies to form helices, whereas Pro, owing to its cyclic structure, is a helix breaker. ... 

Some amino-acid residues are more likely to form a-helices than others. In particular, proline is known as a "helix-breaker" because it prevents the polypeptide chain folding into an a-helix. From examination of a-helices in known protein structures, a table of the probability of a residue being found in a-helix, or other secondary structure, can be constructed. When a protein of unknown structure is studied, the amino-acid sequence can be compared with the table of probabilities and re-... 

Most hydrophobic amino acid crystals produce two straight sequences in two planes, whereas many hydrophilic amino acids have one plane with a straight and one plane with a zig-zag sequence. There is no obvious correlation between packing of the pure amino acids in crystals and favored secondary structures in proteins helix breakers may, for example, form helices in crystals of the pure amino acid. 

Importance Pro is able to participate in a-helices to a much lower extent than other amino acids. It is thus a helix breaker of particular importance for the structure of proteins. Rotation about the amino peptide bond of proline is especially hindered the correct folding of Pro-containing proteins thus appears to be catalyzed by peptidylprolyl cis-fra/u-isomerases (rotamases, EC 5.2.1.8 see FK-506). On account of its presence in gluten, Pro is involved in the Maillard reaction resulting in the typical bread flavor. The inner salt (betaine) of I, l-dimethyl-P. is a widely distributed pyrrolidine alkaloid in plants, e.g., in woundwort (Stachys spp., stachydrin). 

It has long been known that certain types of components can drive the self-assembly of particular stmctures. For example, the amino acid residues alanine and leucine promote a-helix formation when they are present within a polypeptide chain, while glycine and tyrosine are considered "helix breakers. " ... 

On the other hand, the equilibrium constant K indicates the tendency to form helical or nonhelical states. K values in excess of unity denote helix formers K values much less than unity, conversely, indicate coil-forming sequences. With proteins, proline, serine, glycine, and aspartine, for example, are typical helix breakers. Lysine, thyrosine, aspartic acid, threonine, arginine, cysteine, and phenyl alanine act as neither helical breakers or formers, whereas all other a-amino acids are typical helix formers. 

E. Amino acid replacements in the interior of subunits. Replacement of a nonpolar by a polar residue in the hydrophobic interior, or a small residue by a large one can cause instability. Insertion of Pro into a helix causes distortion (Pro is a helix breaker") and instability. 

Blout et al. were the first to report a defined relationship between amino acid sequence and secondary structure of polypeptides Referring to the results of conformational studies on synthetic homopolymers they designated residues with a significant preference for helical regions as helixformers whereas the others were called helix-breakers . 

These experiments emphasized that L-Pro acts as a helix-breaker when inserted into the center part of a peptide of a-helical structure. However, placed at the N-termi-nus, proline behaves like a helix initiator . These findings, in perfect agreement with results obtained from statistical analyses of proteins (see chapter 2.4.1.1), can be rationalized by stereochemical studies on dipeptide units of the type L-Pro-L-X and L-X-L-Pro... 

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