Turn secondary structural elements

Starting from the protein sequence (primary structure) several algorithms can be used to analyze the primary structure and to predict secondary structural elements like beta-strands, turns, and helices. The first algorithms from Chou and Fasman occurred already in 1978. The latest algorithms find e.g., that predictions of transmembrane... 

To prevent insolubility resulting from uncontrolled aggregation of extended strands, two adjacent parallel or antiparallel yS-peptide strands can be connected with an appropriate turn segment to form a hairpin. The / -hairpin motif is a functionally important secondary structural element in proteins which has also been used extensively to form stable and soluble a-peptide y9-sheet arrangements in model systems (for reviews, see [1, 4, 5] and references therein). The need for stable turns that can bring the peptide strands into a defined orientation is thus a prerequisite for hairpin formation. For example, type F or II" turns formed by D-Pro-Gly and Asn-Gly dipeptide sequences have been found to promote tight a-pep-tide hairpin folding in aqueous solution. Similarly, various connectors have been... 

It is interesting that a unique secondary structural element, designated the half-turn, was indentified in preliminary NMR studies of rabbit metallothionein-2 (Wagner etal., 1986). The half-turn element is defined as a type II turn with (f>3 rotated from 90° to -90° its occurrence in the metallothionein-2 structure arises from the constraints placed on the relatively short polypeptide chain by the metal clusters. Although these constraints are not well understood and are certainly difficult to predict, the continued biophysical study of metallothionein-2 will certainly improve our understanding of protein-metal cluster interactions. 

In principle every compound with an amino and a carboxy group can be used for such purpose ranging from simple co-amino acids [e.g., 5-aminopentanoic acid (6-aminovaleric acid) (1, n = 3)]1541 or 6-aminohexanoic acid (e-aminocaproic acid) (1, n = 4)]135,57,4 791 and related derivatives of 3-aminobenzoic acid 14801 or more sophisticated structures. A few examples (1-6) are shown in Scheme 28. Numerous cyclic turn mimetics have been developed in the past years and for details on this subject the reader is directed to Vol. E 22c, Section 12. To explore the rigidification introduced by nonnatural amino acids or equivalent structures into cyclic peptides, a careful NMR conformational analysis is required, since frequently the so-called p-turn mimetics do not enable such turns to be established, conversely other secondary structure elements may be induced.14811... 

The structure of IFN-x was also examined by CD [10]. Analysis of the IFN-x spectra predicts that the secondary structural elements derived from CD spectra indicate approximately 70% a-helix. The remainder of the molecule is either predicted to be random or a combination of (3 sheet and turn. Since it is known that algorithms that predict secondary structures from CD spectra are most accurate at identifying a helices, we are confident that IFN-x is mainly a helical. The CD spectra for the synthetic peptides of IFN-x were also obtained. The peptides IFN-x(l-37), IFN-x(62-92), IFN-x(l 19-150), and IFN-x(139-172) all show the presence of a helix, while IFN-x(34-64) and IFN-x(90-122) are mainly random. The presence of an a helix in the peptides supports the CD analysis of the intact protein and also roughly indicates the location of helical segments. 

To form a globular protein, a polypeptide chain must repeatedly fold back on itself. The turns or bends by which this is accomplished can be regarded as a third major secondary structural element in proteins. Turns often have precise structures, a few of which are illustrated in Fig. 2-24. As components of the loops of polypeptide chains in active sites, turns have a special importance for the functioning of enzymes and other proteins. In addition, tight turns are often sites for modification of proteins after their initial synthesis (Section F). 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

As a key feature of the TASP approach, the template is designed to direct and reinforce the folding of the covalently attached secondary structure elements in the predetermined tertiary structures (Scheme 1), e.g. a four a-helical bundle. The major purpose of artificial turn-inducing mimics is to constrain, when incorporated at the appropriate location, the peptide chain into a semi-rigid, defined, spatial arrangement. 39 8-(Aminomethyl)-5,6,7,8-tetrahydro-2-naphthoic acid (Amhn) is designed to substitute for the central dipeptide unit of a reverse turn and is prepared in a five-step procedure starting from commercially available 4-phen-ylbutanoic acid 40 (Scheme 3). 

Turns are segments between secondary structural elements and are defined as sites in a polypeptide structure where the peptidic chain reverses its overall... 

The a-helix is the most abundant secondary structural element, determining the functional properties of proteins as diverse as a-keratin, hemoglobin and the transcription factor GCN4. The average length of an a-helix in proteins is approximately 17 A, corresponding to 11 amino acid residues or three a-helical turns. In short peptides, the conformational transition from random coil to a-helix is usually entropically disfavored. Nevertheless, several methods are known to induce and stabilize a-helical conformations in short peptides, including ... 

There are different classes of protein sequence databases. Primary and secondary databases are used to address different aspects of sequence analysis. Composite databases amalgamate a variety of different primary sources to facilitate sequence searching efficiently. The primary structure (amino acid sequence) of a protein is stored in primary databases as linear alphabets that represent the constituent residues. The secondary structure of a protein corresponding to region of local regularity (e.g., a-helices, /1-strands, and turns), which in sequence alignments are often apparent as conserved motifs, is stored in secondary databases as patterns. The tertiary structure of a protein derived from the packing of its secondary structural elements which may form folds and domains is stored in structure databases as sets of atomic coordinates. Some of the most important protein sequence databases are PIR (Protein Information Resource), SWISS-PROT (at EBI and ExPASy), MIPS (Munich Information Center for Protein Sequences), JIPID (Japanese International Protein Sequence Database), and TrEMBL (at EBI). ... 

FIGURE 3.4.2 Increments on circular dichroism spectra of secondary structure elements cx-helix (black solid line), (3-sheet (black dashed-dotted line), (3-turn (gray dashed line), poly-L-proline (gray solid line), and random coil (black dashed line). 

This type of hydrogen bonds includes the N-H 0=C interactions which are the most predominant hydrogen bonds in fibrous and globular proteins. Because they are responsible for the formation of the commonly occurring secondary structure elements a-helix, -pleated sheet and / -turn, a large body of much less accurate data is available from protein crystal structures which will be analyzed in Part III, Chap. 19. The N-H 0=C type hydrogen bond is also the most common in the purine and pyrimidine crystal structures (Thble 7.14), and is one of the two important bonds in the base pairing of the nucleic acids. 

Ge<>metry of the Secondary-Structure Elements Helix, Pleated Sheet, and TUrn... 

Because main-chain to main-chain hydrogen bonds in the secondary-structure elements, a-helix, /J-pleated sheet and / -turn, are comparable in character and geometry, they are considered together in the following. 

The above description is a considerable simplification of protein secondary structure possibilities. Thus a number of helix types are possible in addition to the a-helix. Further, particular structured 3-turns exist that are stabilized by hydrogen bonding and link other secondary structure elements. Relatively unstructured coils, loops and random coils can also link a-helical and 3-strand elements. 

Table 10.1 summarizes neural network applications for protein structure prediction. Protein secondary structure prediction is often used as the first step toward understanding and predicting tertiary structure because secondary structure elements constitute the building blocks of the folding units. An estimated 90% or so of the residues in most proteins are involved in three classes of secondary structures, the a-helices, p-strands or reverse turns. Related to the secondary structure prediction are also the prediction of solvent accessibility, transmembrane helices, and secondary structure content (10.2). Neural networks have also been applied to protein tertiary structure prediction, such as the prediction of the backbones or side-chain packing, and to structural class prediction (10.3). 

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