Structure

L-amino acids are combined in proteins by the formation of a bond between the carbon atom of the α-carboxyl group of one amino acid and the nitrogen of the α-amino group of the next. This is the peptide bond. A small number of amino acids (residues) joined in this way are called a peptide, a larger number a polypeptide. The electrons of the double bond of the carbonyl group are delocalised, giving the C–N peptide bond a partial double bond character, which restricts rotation about this bond and influences how polypeptides fold in space. The sequence of amino acids joined by peptides in a polypeptide, the primary sequence or structure, is determined by the sequence of the gene coding for that polypeptide, and in turn determines how the polypeptide folds in three-dimensional space (Figure 4.1). Primary sequence is always written from the free amino terminus on the left to the free carboxyl terminus on the right, which is the direction of protein synthesis. The structure of polypeptides exhibits a hierarchy, with the primary structure being the first level.

The next level of polypeptide or protein structure is the secondary structure (Figure 4.2), which describes some of the folding of the polypeptide in 3D space. Regions of polypeptides can adopt three types of secondary structure determined by the amino acid sequence. The α-helix (Figure 4.2a) has a right-handed thread with 3.6 amino acids per turn and is stabilised by hydrogen bonds between every fourth amino acid formed by the carbonyl and NH groups of peptide bonds. Amino acid side chains point out from the helix. β-strands are pleated structures that hydrogen bond together to form β-sheets with amino acids side chains positioned above or below the plane of the sheet, while the strands can run in the same (parallel) or opposite (anti-parallel) directions. Secondary structure also includes β-turns (Figure 4.2b), consisting of about 4–7 amino acids, which introduce a turn into the backbone of the polypeptide (e.g. between two anti-parallel β-strands). Polypeptides can also include regions lacking in the clearly defined secondary structures described, such as various loops, random coils, or disordered regions. An example of a polypeptide containing mostly α-helix is myoglobin, while some membrane channel proteins contain extensive β-sheets that form a barrel-like structure.

Tertiary structure describes how secondary structures are arranged in space with respect to each other and the overall ‘fold’ of the polypeptide, and is stabilised mainly by hydrophobic interactions. Soluble proteins (Figure 4.3) generally fold to hide hydrophobic amino acid side chains in the interior away from water, while polypeptides resident in membranes (Figure 4.4) tend to have hydrophobic amino acids in the membrane-spanning regions, with side chains facing the interior of the membrane. Many polypeptides fold to create distinct domains, which are associated with a particular function, for example binding ATP, and similar domains can be found in different polypeptides with this function. The final level of protein structure is quaternary and describes how many polypeptide chains are grouped together in the functional protein, held together largely by non-covalent interactions, although inter-chain disulfide bonds between cysteine residues can play a role. Individual polypeptides in proteins are called subunits; although many proteins will have only one subunit many have two, four, or more.