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amino acid residues clustering together to lock water out, leading to a globular tertiary structure; the hydrophobic residues are oriented toward the inside, and the polar and charged residues toward the outside."/>
Figure 2.10 Folding of peptide chains under aqueous conditions leads to a compact globular conformation with a hydrophobic core.
However, the conformation of proteins can easily change if they come into contact with other proteins or contents of the cell. Other examples of protein modifications are phosphorylation (of hydroxyl groups of tyrosine, serine, and threonine) or dephosphorylation that leads to a change in conformation. It is experimentally simple to alter the conformation of a protein using detergents or urea. For example, when globular proteins are dissolved in a 4 M urea solution, the polypeptide chain unfolds (i.e. the protein is denatured). If the urea is removed, the polypeptide chain refolds into the previous conformation (renaturing).
Even though each protein has an individual conformation, when the structures of many proteins are compared, two folding patterns that regularly appear are recognized. These structural elements are:
α‐Helix structures.
β‐Pleated sheet structures.
α‐Helix structures and β‐pleated sheet structures arise from hydrogen bonds between the NH and CO groups in the backbone of the polypeptide chain. Functional groups on the side chains do not take part in these structural elements. Figure 2.11 describes the structure of helices and pleated sheets more precisely. Other structures include loops and random coils.
Figure 2.11 Importance of hydrogen bonds for the construction of α‐helix and β‐sheet structures. (a) The right twisting helix has 3.6 residues per turn. The dotted lines represent the hydrogen bonds between CO and NH groups. (b) The zigzag‐shaped representation of a β‐pleated sheet. Dotted lines symbolize hydrogen bonds. The side chains alternate between being present below and above the folded plane.
Source: Voet et al. (2016). Reproduced with permission of John Wiley and Sons.
A β‐sheet structure element is often found at the inner core of many proteins. The β‐pleated sheet can appear between neighboring polypeptide chains that have the same orientation (parallel chain). When a polypeptide chain folds back on itself and is aligned in parallel, the chains are termed antiparallel chains. In both cases, the chains are being held strongly together by hydrogen bonds (Figure 2.11).
An α‐helix forms when a single peptide chain winds around itself and forms a sturdy cylinder. In doing so, a hydrogen bond forms between each fourth peptide bond (i.e. between the CO group of one peptide bond and the NH group of the other peptide bond). This results in the formation of an ordered helix with a complete turn every 3.6 amino acids. Short α‐helix structures can be found in membrane proteins that possess a transmembrane region. In this case, the α‐helix contains only amino acids with nonpolar residues. The nonpolar residues are oriented toward the outside of the helix and shield the hydrophilic backbone of the peptide chain and interact with the lipophilic components of the phospholipids.
In fibrous proteins (e.g. α‐keratin), two or three longer helices can twist around each other (coiled coil) and form long ropelike structures.
The structure of proteins is very complex, because there are thousands of covalent and noncovalent bonding possibilities between the atoms of the peptide chains and the amino acid residues. Through X‐ray and nuclear magnetic resonance(NMR) analysis, the spatial structures of many hundreds of proteins have been determined. Structure analysis is a challenge not only for basic research but also for applied pharmaceutical research. If the structure or binding sites of a receptor or enzyme are known in detail, it should be possible to design new active substances that have the correct fit and act either as an agonist or as an antagonist. Successes in rational drug design so far concern active substances in the area of AIDS (HIV protease inhibitors; Viracept, Agenerase) and influenza (neuraminidase inhibitors: Relenza, Tamiflu).
There are four structural levels of protein structure:
Primary structure. Primary structure corresponds to the amino acid sequence.
Secondary structure. Secondary structure corresponds to α‐helix and β‐pleated sheet formations.
Tertiary structure. Tertiary structure corresponds to the three‐dimensional conformation of a polypeptide chain.
Quaternary structure. If a protein complex consists of several subunits (i.e. hemoglobin), then the entire structure is referred to as the quaternary structure.
The proteins of a cell usually contain between 50 and 2000 amino acid residues. Theoretically, each of the 20 amino acids can appear at each location of a polypeptide chain. In an oligopeptide, with a length of four amino acids, there are 20 × 20 × 20 × 20 = 160 000 different oligopeptides. The number of possible peptide molecules can be calculated as 20n, where n denotes the chain length. For a protein with the average length of 300 amino acids (Figure 2.12), 20300 = 10390 possible variations are derived. However, not even our universe has that many atoms. From the great number of variants, only a comparatively small number was seemingly realized by nature. Through the course of evolution, many more proteins have been created. However, following natural selection only those proteins that have proven to be of value remain. During the course of evolution, protein families deriving from the first proteins with defined functions have developed through gene duplication. The original sequence has been changed in the new proteins.
Figure 2.12 Size of proteins in yeast (Saccharomyces cerevisiae). The yeast genome project allowed a first estimate of the size of yeast proteins.
During analysis of genome projects, individual structural domains of many proteins have been identified with the help of bioinformatics. Large proteins are usually made up of several functional domain or modules. Domains usually have defined structures and functions (Figures 2.13 and 2.14). They often correspond to the exons in a eukaryotic gene (see Section 4.2). They developed in early evolution, obviously independent of each other. In a later evolutionary phase, the gene sections coding for a domain were newly combined. Through domain shuffling, proteins with new characteristics could thus be created. As a consequence, most proteins can be seen as variants of previously existing proteins or of their domains. Figure 2.13 shows as an example the structure of an Src