Amino helix breaker

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... 

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

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 . 

The secondary amino acid Pro is generally considered an a-helix breaker. Secondary amino acid surrogates, which also mimic the effect of Pro, can potentially disrupt secondary structure formation. They are attractive in SPPS, if the modification which transiently made them secondary amino acid can be removed after peptide chain assembly. This has been used in two synthetic methods. 

The information measure was estimated from statistical analysis of known structures. Robson and Suzuki (1976) considered 25 proteins (i.e., about 4500 residues). Directional information was represented graphically for the different residues. In Fig. 4.7 examples are given for four amino adds taken in the classification of Lewis and co-workers (1971) (i.e., Gly and Pro as helix breakers, Glu as helix former, and Arg as helix indifferent). In Fig, 4.7, the residue considered is taken as zero. Information at —4 is the information which the named residue transmits to any residue, 4 residues away along the sequence in the N-terminal direction independently of the nature of this residue. The information for an a helix, extended structure, and turn was evaluated. 

The linear peptide as observed in its primary structure starts folding on itself because of the interactions among the side chains of the adjacent amino acids. This leads to the formation of different structures, which include (a) helical structure called an alpha helix, (b) stranded folds called beta sheets or beta strands, and (c) random coils. Now, certain criteria can be used to predict the occurrence of these structures in the secondary structure of the protein. This was first established by Chow and Fasman (1978) based on the propensity of certain amino acids associated with these structures, i.e., helix and beta sheet. For example, the amino acids glu, met, ala, and lys are predominantly associated with the helix structure whereas the amino acids val, ile, and tyr are strongly associated with the beta sheet structure. The amino acid leucine is associated with both the helix and the beta sheet. The amino acids glycine and proline occur as breakers of the helix proline usually occurs as the first residue in the helix. Also, asp and glu occurs at the N-terminus, whereas arg and lys occur at the C-terminus. 

The first step in this procedure requires the secondary structural elements to be predicted. In other words, each amino acid must be assigned to one of three classes a-helix, / -strand or coil (i.e. neither helix nor strand) Some approaches also predict whether an amino acid is present in a turn structure. One of the first methods for secondary structure prediction was devised by Chou and Fasman [Chou and Fasman 1978]. Theirs is a statistical method, based upon the observed propensity of each of the 20 amino acids to exist as a-helix, / -strand and coil. These propensities were originaUy determined by analysing 15 protein X-ray structures. The fractional occurrence of each amino acid in each of these three states was calculated, as was the fractional occurrence of the amino acid over all 15 structures. The propensity of that residue for a given t3rpe of secondary structure then equals the ratio of these two values. Each residue was also classified according to its propensity to act as an initiator or as a breaker of a-helices and /3-strands. To predict the secondary structure, the amino acid sequence is searched for potential a-helix or /3-strand initiating... 

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