Specificity and Affinity of Protein Ligand Binding Depend on Molecular Complementarity

Two properties of a protein characterize its interaction with ligands. Specificity refers to the ability of a protein to bind one molecule in preference to other molecules. Affinity refers to the strength of binding. The Kd for a protein-ligand complex, which is the inverse of the equilibrium constant Keq for the binding reaction, is the most common quantitative measure of affinity (Chapter 2). The stronger the interaction between a protein and ligand, the lower the value of Kd. Both the specificity and the affinity of a protein for a ligand depend on the structure of the ligand-binding site, which is designed to fit its partner like a mold. For high-affinity and highly specific interactions to take place, the shape and chemical surface of the binding site must be complementary to the ligand molecule, a property termed molecular complementarity.

The ability of proteins to distinguish different molecules is perhaps most highly developed in the blood proteins called antibodies, which animals produce in response to antigens, such as infectious agents (e.g., a bacterium or a virus), and certain foreign substances (e.g., proteins or polysaccharides in pollens). The presence of an antigen causes an organism to make a large quantity of different antibody proteins, each of which may bind to a slightly different region, or epitope, of the antigen. Antibodies act as specific sensors for antigens, forming antibody-antigen complexes that initiate a cascade of protective reactions in cells of the immune system.

All antibodies are Y-shaped molecules formed from two identical heavy chains and two identical light chains (Figure 3-15a). Each arm of an antibody molecule contains a single light chain linked to a heavy chain by a disulfide bond. Near the end of each arm are six highly variable loops, called complementarity-determining regions (CDRs), which form the antigen-binding sites. The sequences of the six loops are highly variable among antibodies, making them specific for different antigens. The interaction between an antibody and an epitope in an antigen is complementary in all cases; that is, the surface of the antibody's antigen-binding site physically matches the corresponding epitope like a glove

▲ FIGURE 3-15 Antibody structure and antibody-antigen interaction. (a) Ribbon model of an antibody. Every antibody molecule consists of two identical heavy chains (red) and two identical light chains (blue) covalently linked by disulfide bonds. (b) The hand-in-glove fit between an antibody and an epitope on its antigen—in this case, chicken egg-white lysozyme. Regions where the two molecules make contact are shown as surfaces. The antibody contacts the antigen with residues from all its complementarity-determining regions (CDRs). In this view, the complementarity of the antigen and antibody is especially apparent where "fingers" extending from the antigen surface are opposed to "clefts" in the antibody surface.

(Figure 3-15b). The intimate contact between these two surfaces, stabilized by numerous noncovalent bonds, is responsible for the exquisite binding specificity exhibited by an antibody.

The specificity of antibodies is so precise that they can distinguish between the cells of individual members of a species and in some cases can distinguish between proteins that differ by only a single amino acid. Because of their specificity and the ease with which they can be produced, antibodies are highly useful reagents in many of the experiments discussed in subsequent chapters.

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