MfenJw and Strong Hands Determine Macromolecular Structure

FIGURE 5-5 Peptide bond. The brackets indicate the two amino acid residues thai are joined by a peptide bond

which the single-polypeptide enzyme ribonuclease was subjected to harsh conditions that interfere with hydrogen bonding and other weak chemical interactions leading to the complete denaturation (or unfolding) of the polypeptide. When the denatured ribonuclease was restored to conditions that allow the formation of weak chemical bonds, the enzyme rapidly regained both its normal three-dimensional structure and RNA cleaving activity. For a description of how protein structures are worked out experimentally, see Box 5-1, Determination of Protein Structure.

a Helices and P Sheets Are the Common Forms of Secondary Structure

The most stable arrangement of a polypeptide backbone is the a helix. This is a right-handed helix, repeating every 5.4 A along the helical axis (Figure 5-8). This structure is preferred because the peptide backbone has favorable ef> and angles that accommodate a regular pattern of hydrogen bonding between carbonyl and imino groups on the same chain. The hydrogen-bonding potential of the peptide backbone is fully utilized to slablizo the structure. As a consequence of the precise geometry of the polypeptide chain, each turn of the a helix has 3.6 amino acids. If, for example, four amino acids were used per turn, the hydrogen bonds would not lie so neatly formed, nor would the individual backbone atoms fit together so well.

Many amino acid sequences can adopt an a helical secondary-structure. This is because the structure of the a helix is stabilized by contacts between the nearly universal backbone atoms of the carbonyl and imino groups in the polypeptide chain. The only amino acid that lacks these atoms is proline, which cannot participate as a donor in the hydrogen bonding that stabilizes the helix because of its cyclic chemical structure. Thus, proline is a helix-breaking residue. Although their structures do not prevent it, glycine, tyrosine, and serine are also rarely found in a helices. Another consequence of the fact that a helices are constructed through exclusively backbone contacts is that the side chains project away from the helix. This puts these side chains in an ideal position to interact with another region of the protein or another macromolecule, such as DNA.

The second common secondary structural element is the p sheet (Figure 5-9). In contrast to the a helix, the p sheet is a highly extended form of the polypeptide backbone. Stablization of the (3 sheet structure comes from alignment of regions of polypeptide in this extended

FIGURE 5-6 c|> and i|j angles of rotation about the Co-N and Ca-C bonds. The shaded areas represent the planes of the peptide bonds. (Source: Illustration, Irving Gets. Rights owned by Howard Hughes Medical Institute. Not to be reproduced without permission.)

primary secondary quaternary tertiary

primary secondary quaternary tertiary

FIGURE 5-7 Four levels of protein structure. (Source: Adapted from Branden C and Tooïe À 1999. Introduction to protein structure, 2nd edition, p. 3. fig Î 1.)

Box 5-1 Détermination of Protein Structure

There are two principal methods to determine the three-dimensional structure of proteins. The first to be developed was X-ray crystallography. This method relies on the formation of highly ordered crystals of pure protein. As with the original diffraction studies of DNA fibers, the irradiation of protein crystals with high-energy X-rays results in diffraction patterns that are related to the structure of the protein. More recently, nuclear magnetic resonance techniques have been developed to elucidate the conformation of smaller proteins. This technique exploits the magnetic properties of certain atoms (such as 'H) to monitor how neighboring atoms influence each other. This information can be used to determine the relative location of specific atoms within the polypeptide chain and these distances predict the overall structure of the protein (see figure 5-7).

In principle it should be possible to predict a protein's three-dimensional structure from its primary amino acid sequence, because, after all, that information is sufficient for a protein to adopt s unique conformation. Although progress is being made in the prediction of protein structure based on amino acid sequence, the full determination of the energetic constraints of a particular sequence is still beyond the most powerful computational approaches. Nevertheless, prediction of certain secondary structural elements (such as the common a helix structure introduced below) is becoming increasingly reliable.

The increasingly large number of available expert mentally-determined structures has provided an important resource for making protein structure predictions based on amino acid sequence. These atomic structures have helped to define families of amino acid sequences that share related three-dimensional shapes. By tompanng the sequences of proteins of unknown structure with those that have been determined, it is often possible to make structural predictions based on the identified similarity. Combining this information with computer algorithms that predict secondary structures is proving to be a powerful method for predicting how proteins fold. The long-term outlook is that these approaches will allow at least an approximate structure to be predicted for any protein from its primary sequence alone.

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