Overall Folding of a Polypeptide Chain Yields Its Tertiary Structure

Tertiary structure refers to the overall conformation of a polypeptide chain—that is, the three-dimensional arrangement of all its amino acid residues. In contrast with secondary structures, which are stabilized by hydrogen bonds, tertiary structure is primarily stabilized by hydrophobic interactions between the nonpolar side chains, hydrogen bonds between polar side chains, and peptide bonds. These stabilizing forces hold elements of secondary structure—a helices, p strands, turns, and random coils—compactly together. Because the stabilizing interactions are weak, however, the tertiary structure of a protein is not rigidly fixed but undergoes continual and minute fluctuation. This variation in structure has important consequences in the function and regulation of proteins.

Different ways of depicting the conformation of proteins convey different types of information. The simplest way to represent three-dimensional structure is to trace the course of the backbone atoms with a solid line (Figure 3-5a); the most complex model shows every atom (Figure 3-5b). The former, a Ca trace, shows the overall organization of the polypeptide chain without consideration of the amino acid side chains; the latter, a ball-and-stick model, details the interactions between side-chain atoms, which stabilize the protein's conformation, as well as the atoms of the backbone. Even though both views are useful, the elements of secondary structure are not easily discerned in them. Another type of representation uses common shorthand symbols for depicting secondary structure—for example, coiled ribbons or solid cylinders for a helices, flat ribbons or arrows for p strands, and flexible

M FIGURE 3-5 Various graphic representations of the structure of Ras, a monomeric guanine nucleotide-binding protein. The inactive, guanosine diphosphate (GDP)-bound form is shown in all four panels, with GDP always depicted in blue spacefill. (a) The Ca backbone trace demonstrates how the polypeptide is packed into the smallest possible volume. (b) A ball-and-stick representation reveals the location of all atoms. (c) A ribbon representation emphasizes how p strands (blue) and a helices (red) are organized in the protein. Note the turns and loops connecting pairs of helices and strands. (d) A model of the water-accessible surface reveals the numerous lumps, bumps, and crevices on the protein surface. Regions of positive charge are shaded blue; regions of negative charge are shaded red.

thin strands for turns and loops (Figure 3-5c). This type of representation makes the secondary structures of a protein easy to see.

However, none of these three ways of representing protein structure convey much information about the protein surface, which is of interest because it is where other molecules bind to a protein. Computer analysis can identify the surface atoms that are in contact with the watery environment. On this water-accessible surface, regions having a common chemical character (hydrophobicity or hydrophilic-ity) and electrical character (basic or acidic) can be mapped. Such models reveal the topography of the protein surface and the distribution of charge, both important features of binding sites, as well as clefts in the surface where small molecules often bind (Figure 3-5d). This view represents a protein as it is "seen" by another molecule.

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