Summary of Amino Acid
You should be aware of how the following properties of amino acids are important
in the context of protein structure:
A general principle concerning packing in proteins can be highlighted by
likening a folded protein to a three-dimensional jigsaw. The interiors of
proteins have a similar packing density to organic solids; this packing is
due to complementary van der Waals surfaces coming into contact upon folding
of the polypeptide(s), filling up most of the space in the interior. It is
the close fitted-packing which confers rigidity to the structure.
Therefore, if a mutation leads to the replacement of a small side chain by
a large one, the folded conformation will tend not to be able to accommodate
the new residue. On the other hand, cavities in the structure are unfavourable,
so replacement of a large side chain by a small side chain will also tend
to destabilize the fold (although cavities might be filled by solvent molecules,
depending on the nature of the groups lining them).
This table gives volumes
(cubic Å) and surface areas (square Å) (
Ron Beavis, Protein
Chemistry Lab, Skirball Institute)
Asp, Glu (one negative charge), Lys and Arg (one positive) are ionized under
most physiological conditions; His is positively charged or neutral depending
on its local environment. Refer to the
A specific type of interaction is that which occurs between 2 charged groups
of opposite sign: these constitute a salt bridge (or 'ion pair').
There is typically 1 ion pair per approximately 30 protein residues. A less
specific property concerns the net charge of a protein. Proteins are found
to be most stable at or near the isoelectric point (i.e. at which
the net charge is zero).
Charged and neutral polar side chains participate in hydrogen bonds, both
with each other, with the main chain polar atoms and with solvent.
Ser and Thr have sp3-hybridized hydroxyl groups; they can act as a
donor in one hydrogen bond, and as an acceptor in two.
Tyr has an sp2-hybridized hydroxyl group (the CZ-OH
bond has partial double-bonded character), which can act as a donor in one
hydrogen bond, and as an acceptor in another.
Asp and Glu each have two sp2-hybridized carboxyl oxygens; each
CG-OD or CD-OE bond has a partial double bond
character. Each oxygen can accept a hydrogen in two hydrogen bonds.
Asn and Gln have a carbonyl oxygen (C=O bond), which can act as an acceptor
in two hydrogen bonds, while the amide nitrogen is sp2-hybridized,
and can donate each of the two hydrogens in a hydrogen bond.
His has two imidazole nitrogens, either or both of which is protonated. Each
of these (ND1 or NE2) can act as an acceptor in a single hydrogen
bond if it is unprotonated, or as a donor in a single hydrogen bond if it
Arg has a guanadinium group, which is usually protonated, and is planar:
the carbon atom is sp2-hybridized. Each of the two -NH2 groups can
donate two hydrogens, and the -NH group one.
Lys can donate three protons in hydrogen bonds: the NZ atom is
Trp can donate a hydrogen in a single hydrogen bond. Its nitrogen atom is
The aliphatic side chains Ala, Val, Leu and Ile (and Gly) contain no polar
atoms, and therefore interact less favourably with water than they do with
other apolar groups. A general feature of globular proteins is that such
hydrophobic residues are found in the protein interior, while polar
residues occur on the surface. In this respect, protein folding may be roughly
compared to the formation of lipid micelles in aqueous solution- the chain
becomes arranged such that apolar groups are buried, and polar groups exposed.
However, bear in mind that such a clear-cut arrangement is not possible for
a polypeptide chain. All residues have main polar chain atoms (N and carbonyl
O), and the manner in which their hydrogen bonding capacity is satisified
within the protein interior is the foundation for higher levels of structure
as will be covered later. On the other hand, several charged and neutral
polar side chains have significant apolar surface area.
Nevertheless, hydrophobicity is a very important factor in protein stability;
indeed the "hydrophobic effect" is believed to play a fundamental role in
the spontaneous folding of proteins. This will be covered later in more
Pro is also aliphatic, but has special conformational properties relating
to its location in proteins. Not only aliphatic side chains are hydrophobic:
although the sulphur-containing Met side chain has a dipole moment, it is
also of apolar character. Disulphide bonds formed by Cys residues (see below)
also have apolar surface area. The Phe side chain is strongly hydrophobic,
even though its delocalized pi-electron system can take part in weak
electrostatic interactions. Trp has the largest side chain, most of which
has a non-polar surface, despite the polar N atom. In the same way, the Tyr
side chain is of partly hydrohobic character.
PPS Consultant Simon Brocklehurst describes
Packing in Hydrophobic Cores (this also requires some knowledge of higher
levels of structure).
The capacity of the delocalized electrons in aromatic side chains to participate
in relatively weak electrostatic interactions has been referred to above.
However, in the context of proteins, there is a tendency for aromatic side
chains to be 'stacked' against amide and amino groups, rather than accepting
protons from them in 'hydrogen bonds'.
Conformationally Unusual Side Chains
Steric hindrance, or the lack of it, means that Pro and Gly play special
roles in polypeptide conformation; refer to
Jon Cooper's material. Steric
constraints are covered in more detail in the next section of the course.
A pair of Cys residues can form a disulphide bond (also known as a
cystine bridge) by the oxidation of their side chains. This was the
subject of a
by Darren Fast (Univ.Wisconsin, USA) during the 1995 VSNS-PPS course.
Last updated 9th Oct'96