Protein structure - Pharmaceutical Biotechnology: Concepts and Aapplications - page 19

The R groups of the non-polar, alipathic amino acids (Gly, Ala, Val, Leu, Ile and Pro) are devoid
of chemically reactive functional groups. These R groups are noteworthy in that, when present in
a polypeptide's backbone, they tend to interact with each other non-covalently (via hydrophobic
interactions). These interactions have a signifi cant stabilizing infl uence on protein conformation.
Glycine is noteworthy in that its R group is a hydrogen atom. This means that the -carbon of glycine

is not asymmetric, i.e. is not a chiral centre. (To be a chiral centre the carbon would have to have four
different chemical groups attached to it; in this case, two of its four attached groups are identical.) As
a consequence, glycine does not occur in multiple stereo-isomeric forms, unlike the remaining amino
acids, which occur as either D or L isomers. Only L -amino acids are naturally found in polypeptides.
The side chains of the aromatic amino acids (Phe, Tyr and Trp) are not particularly reactive
chemically, but they all absorb ultraviolet (UV) light. Tyr and Trp in particular absorb strongly at
280 nm, allowing detection and quantifi cation of proteins in solution by measuring the absorbance
at this wavelength.
Of the six polar but uncharged amino acids, two (cysteine and methionine) are unusual in
that they contain a sulfur atom. The side chain of methionine is non-polar and relatively unre-
active, although the sulfur atom is susceptible to oxidation. In contrast, the thiol (!C!SH)
portion of cysteine's R group is the most reactive functional group of any amino acid side chain.
In vivo , this group can form complexes with various metal ions and is readily oxidized, forming
'disulfi de linkages' (covalent linkages between two cysteine residues within the same or even
different polypeptide backbones). These help stabilize the three-dimensional structure of such
polypeptides. Interchain disulfi de linkages can also form, in which cysteines from two different
polypeptides participate. This is a very effective way of covalently linking adjacent polypeptides.
Of the four remaining polar but uncharged amino acids, the R groups of serine and threo-
nine contain hydroxyl (OH) groups and the R groups of asparagine and glutamine contain amide
(CONH 2 ) groups. None are particularly reactive chemically; however, upon exposure to high tem-
peratures or extremes of pH, the latter two can deamidate, yielding aspartic acid and glutamic acid
respectively.
Aspartic and glutamic acids are themselves negatively charged under physiological conditions.
This allows them to chelate certain metal ions, and also to markedly infl uence the conformation
adopted by polypeptide chains in which they are found.
Lysine, arganine and histidine are positively charged amino acids. The arganine R group consists
of a hydrophobic chain of four !CH 2 groups ( Figure 2.1), capped with an amino (NH 2 ) group,
which is ionized (NH 3 ) under most physiological conditions. However, within most polypeptides
there is normally a fraction of un-ionized lysines, and these (unlike their ionized counterparts)
are quite chemically reactive. Such lysine side chains can be chemically converted into various
analogues. The arganine side chain is also quite bulky, consisting of three CH 2 groups, an amino
group (!NH 2 ) and an ionized guanido group ("NH 2 ). The 'imidazole' side chain of histidine
can be described chemically as a tertiary amine (R 3 !N), and thus it can act as a strong nucle-
ophilic catalyst (the nitrogen atom houses a lone pair of electrons, making it a 'nucleus lover' or
nucleophile; it can donate its electron pair to an 'electron lover' or electrophile). As such, the his-
tidine side chain often constitute an essential part of some enzyme active sites.
In addition to the 20 'common' amino acids, some modifi ed amino acids are also found in several
proteins. These amino acids are normally altered via a process of post-translational modifi cation
(PTM) reactions (i.e. modifi ed after protein synthesis is complete). Almost 200 such modifi ed
amino acids have been characterized to date. The more common such modifi cations are discussed
separately in Section 2.5.

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