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The third characteristic necessary for a compound to be immunogenic is a certain degree of physicochemical complexity. Thus, for example, simple molecules such as homopolymers of amino acids (e.g., a polymer of lysine with a molecular weight of 30,000 Da) are seldom good immunogens. Similarly, a homopolymer of poly‐γ‐D‐glutamic acid (the capsular material of Bacillus anthracis) with a molecular weight of 50,000 Da is not immunogenic. The absence of immunogenicity is because these compounds, although of high molecular weight, are not sufficiently chemically complex. However, if the complexity is increased by attaching various moieties (such as dinitrophenol or other low molecular weight compounds), which by themselves are not immunogenic, to the ε amino group of polylysine, the entire macromolecule becomes immunogenic. The resulting immune response is directed not only against the coupled low molecular weight compounds but also against the high molecular weight homopolymer. In general, an increase in the chemical complexity of a compound is accompanied by an increase in its immunogenicity. Thus copolymers of several amino acids, such as polyglutamic, alanine, and lysine (poly‐GAT), tend to be highly immunogenic.

Because many immunogens are proteins, it is important to understand the structural features of these molecules. Each of the four levels of protein structure contributes to the molecule’s immunogenicity. The acquired immune response recognizes many structural features and chemical properties of compounds. For example, antibodies can recognize various structural features of a protein, such as its primary structure (the amino acid sequence), secondary structures (the structure of the backbone of the polypeptide chain, such as an α‐helix or β‐pleated sheet), and tertiary structures (formed by the three‐dimensional configuration of the protein, which is conferred by the folding of the polypeptide chain and held by disulfide bridges, hydrogen bonds, hydrophobic interactions, etc.) (Figure 5.1). They can also recognize quaternary structures (formed by the juxtaposition of separate parts, if the molecule is composed of more than one protein subunit) (Figure 5.2).