Below are listed the names of each of the set of 20 "standard" amino acids, followed by their three- and one-letter abbreviations, and a short description of their structure and (in some cases) some notable feature. The links are to the biochemistry dictionary, and open a separate window that contains more information on a particular amino acid.

Glycine (Gly, G) - an achiral amino acid that confers extra flexibility upon a polypeptide chain.

Amino acids with non-polar, aliphatic side chains:

Alanine (Ala, A) - side chain consists of a single methyl group.
Valine (Val, V) - three-carbon, β-branched side chain.
Leucine Leu, L) - four carbon, γ-branched side chain.
Isoleucine (Ile, I) - four carbon, β-branched side chain. β-carbon is chiral.
Proline (Pro, P) - three-carbon side chain forms five-membered ring incorporating main chain.

Amino acids with aromatic side chains:

Phenylalanine (Phe, F) - side chain is a benzene ring attached to β-methylene group.
Tyrosine (Tyr, Y) - the same as Phe, except phenyl ring has a p-hydroxy substituent
Tryptophan (Trp, W) - side chain is the very bulky indole double ring attached to β-methylene group.

Amino acids with hydroxyl groups:

Serine (Ser, S) - like alanine, except substituted with -OH
Threonine (Thr, T) - has an extra methyl group - as well as a hydroxyl group - attached to the (chiral) β-carbon.

Sulfur-containing amino acids:

Methionine - considered to be non-polar; has thioether side chain
Cysteine - like alanine, except substituted with thiol group. Most reactive side chain.

Lysine and arginine: amino acids with basic side chains

Lysine (Lys, K) is basic due to an amine functional group - often denoted as the ε (epsilon) amino group - that is at the end of a straight chain of four methylene groups.

Arginine (Arg, R) possesses a guanidino group attached to a three-carbon chain.

The side chains of both of these amino acids have relatively high pKa values, so these residues typically will be positively charged in proteins.

Histidine: an "ambidextrous" amino acid

Histidine (His, H) is one of the most interesting amino acids because of the variety of roles it can play in protein function, especially as a key residue in many enzyme active sites. Of all the ionizable side chains, the typical pKa of the imidazole ring of His is closest to a neutral pH. Studies of model compounds have established a range of 6.0 - 7.0 for the intrinsic pKa of the histidine side chain.

The neutral form of the imidazole ring can exist in two different tautomric forms: with hydrogen on the δ1 nitrogen or with hydrogen on the ε2 nitrogen. The pKa of the ε2 nitrogen has been shown in 13-C NMR studies of a model compound to be about 0.6 pH units higher than that of the δ1 nitrogen, so in the absence of countervailing environmental effects, the form on the right will tend to predominate.

"Acidic" amino acids and their amides: Aspartate, glutamate, asparagine, and glutamine

The side chains of side chains of aspartate (Asp, D) and glutamate (Glu, E) both contain an acidic carboxyl group. Thus these side chains normally exist in their ionized (anionic) carboxylate form at physiological pH. The Asp side chain [ structure ] has a single methylene at the β position, followed by the carboxyl functionality. Glu [ structure ] possesses an extra carbon (γ) in its side chain. Although they differ by only one methylene group, this seemingly slight difference has more pronounced effects on their chemical and functional properties than one might initially suppose.

Asparagine (Asn, N) and glutamine (Gln, Q) are the amides of the side chain carboxyl groups of Asp and Glu respectively. As amides, they no longer carry a charge, but are polar and can act as both H-bond donors and acceptors. Structures: [ asparagine ] [ glutamine ]

Intrinsic pK_a values for ionizable groups in proteins

The pKa values for ionizable groups in proteins depend on a number of factors, especially local environment (see below). However, studies employing model compounds - representative of an isolated amino acid residue, for example - have been interpreted as defining a range of pH values containing an "intrinsic" pKa for a given group. There is a rough correspondence between the values given here and those in textbooks (e.g. Table 4.1, pp.76-77 in Ref.1), but you will notice some differences. The goal is not to memorize tables of pKa values, but to at least have a good feel for approximate values, and certainly a knowledge of which residues/groups are acidic, and the relative order of basicity of other ionizable groups. In addition to this, a healthy appreciation of the sensitivity of these values to local enviromnments within the context of folded proteins is desirable. Instilling this is the goal of the next section.

Perturbed or "anomalous" pK_a values

As has already been suggested, the intrinsic pKa values for ionizable groups are no guarantee that a particular residue in a particular protein will be in a particular ionization state at a pH consistent with its physiologically relevant structure and function. Some pKa values are perturbed significantly from their intrinsic values, and these "anomalous" values are furthermore demonstrably important for the proper function of a protein in some cases.

To illustrate the idea, consider an aspartate residue in a neutral (pH 7) aqueous environment with a "normal" pKa. The residue will be overwhelmingly ionized. By plugging in values for the pKa of the residue, the pH of the medium, the Henderson-Hasselbalch equation can be used to calculate the proportion of ionized to unionized forms of the residue. The top half of the figure below illustrates the situation.

Now consider the influence of a nearby negative charge on the ionization of our hypothetical residue. The presence of the negative charge makes the ionization much less favorable, shifting the equilibrium to the left. The greater the shift in the equilibrium, the more the pKa is raised from its intrinsic value. In the extreme case illustrated, the amounts of both forms of the residue are equal, and the pKa has been perturbed upward by three units.

An example of this effect where the residue with an anomalous pKa is directly involved in the protein's function is provided by lysozyme. Lysozyme is an enzyme produced by a variety of organisms that hydrolyzes the polysaccharide component of the peptidoglycan cell walls of many types of bacteria. The mechanism of lysozyme depends on two acidic residues, Asp52 and Glu35. Asp52 has a normal pKa. Its negative charge stabilizes a developing positive charge as the reaction proceeds through a oxonium ion intermediate. However, Glu35 has an anomalously high pKa (its pKa is thought to be about 6.5), keeping it more in the protonated form. The unionized form of Glu35 donates a hydrogen ion to the oxygen of the glycosidic linkage, assisting the breaking of the bond between sugar residues. Glu35 would not be so effective in this role if its pKa was normal.

Learning objectives

• Draw structures for all 20 of the canonical standard set of amino acids.
• Predict pKa values for ionizable groups in peptides and proteins: ionizable side chains, N- and C-termini, groups arising from common post translational modifications.
• Predict the general appearance of titration curves for amino acids, peptides, and proteins.
• Predict the direction of shift of intrinsic pKa by perturbations such as a nearby charge or a more nonpolar environment.

Page updated 9-4-09

References:

1. Donald Voet, Judith G. Voet, Charlotte W. Pratt Fundamentals of Biochemistry (3rd edition) Ch.4, pp.74-89.
2. Creighton, TE. Proteins: Structure and Molecular Properties (2nd ed, 1993. Freeman)
3. Harris TK, Turner GJ. (2002). Structural basis of perturbed pKa values of catalytic groups in enzyme active sites (Review). IUBMB Life, 53: 85.