Twenty kinds of side chains varying in size, shape, charge, hydrogen-bonding capacity, hydrophobic character, and chemical reactivity are commonly found in proteins. Many of these properties are conferred by functional groups (Table 2.1). The amino acid functional groups include alcohols, thiols, thioethers, carboxylic acids, carboxamides, and a variety of basic groups. Most of these groups are chemically reactive.

All proteins in all species—bacterial, archaeal, and eukaryotic—are constructed from the same set of 20 amino acids with only a few exceptions. This fundamental alphabet for the construction of proteins is several billion years old. The remarkable range of functions mediated by proteins results from the diversity and versatility of these 20 building blocks.

Although there are many ways to classify amino acids, we will assort these molecules into four groups, on the basis of the general chemical characteristics of their R groups:

The amino acids having side chains consisting only of hydrogen and carbon are hydrophobic. The simplest amino acid is glycine, which has a single hydrogen atom as its side chain. With two hydrogen atoms bonded to the α-atom, glycine is unique in being achiral. Alanine, the next simplest amino acid, has a methyl group (–CH₃) as its side chain (Figure 3.3). The three-letter abbreviations and one-letter symbols under the names of the amino acids depicted in Figure 3.3 and in subsequent illustrations are an integral part of the vocabulary of biochemists.

Larger aliphatic side chains are found in the branched-chain amino acids valine, leucine, and isoleucine. Methionine contains a largely aliphatic side chain that includes a thioether (–S–) group. The different sizes and shapes of these hydrocarbon side chains enable them to pack together to form compact structures with little empty space. Proline also has an aliphatic side chain, but it differs from other members of the set of 20 in that its side chain is bonded to both the α-carbon and the nitrogen atom. Proline markedly influences protein architecture because its ring structure makes it more conformationally restricted than the other amino acids.

Two amino acids with simple aromatic side chains are also classified as hydrophobic (Figure 3.3). Phenylalanine, as its name indicates, contains a phenylring attached in place of one of the methyl hydrogen atoms of alanine. Tryptophan has an indole ring joined to a methylene (—CH₂—) group; the indole group comprises two fused rings and an NH group.

The hydrophobic amino acids, particularly the larger aliphatic and aromatic ones, tend to cluster together inside the protein away from the aqueous environment of the cell. This tendency of hydrophobic groups to come together is called the hydrophobic effect and is the driving force for the formation of the unique three-dimensional architecture of water-soluble proteins. The different sizes and shapes of these hydrocarbon side chains enable them to pack together to form compact structures with little empty space.

The next group of amino acids that we will consider are those that are neutral overall, yet they are polar because the R group contains an electronegative atom that hoards electrons. Three amino acids, serine, threonine, and tyrosine, contain hydroxyl (—OH) groups (Figure 3.4). The electrons in the O—H bond are attracted to the oxygen atom, making it partly negative, which in turn makes the hydrogen partly positive. Serine can be thought of as a version of alanine with a hydroxyl group attached to the methyl group, whereas threonine resembles valine with a hydroxyl group in place of one of the valine methyl groups. Tyrosine is similar to phenylalanine but contains a hydrophilic hydroxyl group attached to the large aromatic ring. The hydroxyl groups on serine, threonine, and tyrosine make them more hydrophilic (water loving) and reactive than their respective nonpolar counterparts, alanine, valine, and phenylalanine. Cysteine is structurally similar to serine but contains a sulfhydryl, or thiol (—SH), group in place of the hydroxyl group. The sulfhydryl group is much more reactive than a hydroxyl group and can completely lose a proton at slightly basic pH to form the reactive thiolate group. Pairs of sulfhydryl groups in close proximity may form disulfide bonds—covalent bonds that are particularly important in stabilizing some proteins, as will be discussed in Chapter 4. In addition, the set of polar amino acids includes asparagine and glutamine, which contain a terminal carboxamide.

We now turn to amino acids having positively charged side chains that render these amino acids highly hydrophilic (Figure 3.5). Lysine and arginine have long side chains that terminate with groups that are positively charged at neutral pH. Lysine is topped by an amino group and arginine by a guanidinium group. Note that the R groups of lysine and arginine have dual properties—the carbon chains constitute a hydrocarbon backbone, similar to the amino acid leucine, but the chain is terminated with a positive charge. Such combinations of characteristics contribute to the wide array of chemical properties of amino acids.

Histidine contains an imidazole group, an aromatic ring that also can be positively charged. With a pK_a value near 6, the imidazole group of histidine is unique in that it can be uncharged or positively charged near neutral pH, depending on its local environment (Figure 3.6). Indeed, histidine is often found in the active sites of enzymes, where the imidazole ring can bind and release protons in the course of enzymatic reactions.

The two amino acids in this group, aspartic acid and glutamic acid, have acidic side chains that are usually negatively charged under intracellular conditions (Figure 3.7). These amino acids are often called aspartate and glutamate to emphasize the presence of the negative charge on their side chains. In some proteins, these side chains accept protons, which neutralize the negative charge. This ability is often functionally important. Aspartate and glutamate are related to asparagine and glutamine in which a carboxylic acid group in the former pair replaces a carboxamide in the latter pair.

Seven of the 20 amino acids—tyrosine, cysteine, arginine, lysine, histidine, and aspartic and glutamic acids—have readily ionizable side chains. These seven amino acids are able to form ionic bonds as well as to donate or accept protons to facilitate reactions. The ability to donate or accept protons is called acid–base catalysis and is an important chemical reaction for many enzymes. We will see the importance of histidine as an acid–base catalyst when we examine the protein-digesting enzyme chymotrypsin in Chapter 8. Table 3.1 gives the equilibria and typical pK_a values for the ionization of the side chains of these seven amino acids.