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Encyclopedia of Physical Science and Technology EN013D-616 July 27, 2001 12:5

192 Protein Structure

adopt a well-defined three-dimensional structure in solu- There are four classes of amino acids specified by the
tion that is essential for protein function. Indeed unfolding geneticcode:(1)aliphaticaminoacids,(2)aromaticamino
or denaturation of a protein typically leads to a loss of bi- acids, (3) polar amino acids, and (4) charged amino acids.
ological activity. These groups of amino acids provide the range of proper-
The amino acid sequence of a protein contains all ties necessary to create a stable, functional folded protein.
of the information necessary to dictate its final three- As discussed elsewhere the primary driving force in
dimensional structure or fold. In many cases small pro- protein folding and protein structure is the hydrophobic ef-
teins can be unfolded and refolded in vitro without loss fect. This serves to sequester the hydrophobic side chains
of activity. In more complex proteins, chaparones are fre- away from the bulk solvent. Once folded a typical pro-
quently necessary to allow a protein to reach its properly tein is a densely packed entity that contains few holes
folded or correct three-dimensional state. Chaparones in larger than a water molecule. The aliphatic amino acids
these instances recognize an incorrectly unfolded protein which include glycine, alanine, valine, leucine, isoleucine,
and provide an energetically favorable pathway, through and proline provide the range of small hydrophobic amino
the hydrolysis of ATP, for the protein to unfold and refold acids necessary to fill the gaps in the interior of the pro-
to reach its functional state. Even in these cases, the struc- tein. Glycine and proline serve special roles in protein
ture of the protein is dictated by its amino acid sequence. structure. Glycine is the smallest amino acid and is unique
In principle, it should be possible to deduce the struc- because it lacks a side chain. This gives it more conforma-
ture of a protein from its amino acid sequence. At this tional freedom than any other amino acid. Glycine is often
time, it is not possible to perform ab initio structure pre- found in turns and loops where other amino acids would be
diction with any great success. As such protein structure sterically unacceptable. It is also found where secondary
prediction remains one of the major problems in biology. structural elements intersect and other side chains would
Progress in structure prediction has been made through the introduce molecular collisions. In contrast proline is un-
combination of sequence and structural similarities. This usual because it is conformationally restricted. As such
offers hope that with the knowledge of sufficient structures it is often found in turns since it introduces an inherent
across a wide range of organisms it should be possible to kink in the polypeptide chain without any entropic cost
generate the structure of all unknown proteins. Although to protein folding. Proline is also unique in that it is the
there is still much to be learned about protein structure, only amino acid (or technically an “imino acid”) that is
a series of fundamental features, folding rules, and struc- commonly found to form a cis peptide bond between it-
tural motifs have been observed in many of the three- self and the residue that precedes it in the polypeptide
dimensional structures determined to date. These common chain. In this instance the energy barrier to rotation is con-
features arise as a consequence of the amino acids used to siderably less than all other peptide bonds (13 kcal/mol
build the proteins, the peptide bonds that join the amino vs ∼20 kcal/mol). This post-translational conformational
acids, and the thermodynamic factors that control protein modification often represents a slow step in protein
stability. These common threads in protein structure are folding.
described in the following. Phenylalanine, tyrosine, and tryptophan are large aro-
matic residues that are normally found buried in the inte-
rior of a protein and are important for protein stability. Ty-
II. AMINO ACIDS rosine has special properties since its hydroxyl side chain
may function as a powerful nucleophile in an enzyme ac-
All proteins are synthesized from the 20 α-amino acids tive site (when ionized) and is a common site for phos-
specified by the genetic code as shown in Fig. 1. The phorylation in cell signaling cascades. Tryptophan has the
nature of an amino acid is determined by the “side- largest side chain and is the least common amino acid in
chain” attached to the α-carbon (Table I). All of these proteins. It has spectral properties that make it the best
amino acids, except for glycine which carries two hydro- inherent probe for following protein folding and confor-
gens on its α-carbon, have a chiral center located at the mational changes associated with biochemical processes.
α-carbon. Thus the amino acids exist as either the L- or The polar amino acids include serine, threonine, cys-
D-isomers. Only the L-stereoisomer is utilized in protein teine, methionine, asparagine, and glutamine. These are an
biosynthesis (Fig. 2). This introduces chirality into all pro- important class of amino acids since they provide many
tein molecules that is the source of most of the asymmetric of the functional groups found in proteins. Serine often
features found in protein structures. The use of only one of serves as a nucleophile in many enzyme active sites, and
the two stereoisomers of the amino acids also establishes is best known for its role in the serine proteases. Both
a structural uniqueness that is essential for biochemical serine and threonine are sites of phosphorylation and gly-
specificity. cosylation which are important for enzyme regulation and