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By Hirra Hussain (University of Manchster)

Proteins are flexible and dynamic macromolecules that come in a variety of shapes and sizes, and have a very important role in biological processes. Proteins have a function in almost all processes within cells and the body such as cell signalling, metabolism, the cell cycle and many more.

Protein structure

Proteins have four levels of structure summarised in Figure 1.

• The first level of the protein structure is the primary structure which is the amino acid sequence. The sequence of amino acids is based upon the codon sequence, a codon being a unit of three nucleotides in the DNA or RNA sequence. In cells there are twenty common amino acids that are used in the synthesis of proteins. Each amino acid also has a unique side chain giving it specific properties; in addition they have an amino (N-terminus) and carboxylate (C-terminus) group which form peptide bonds with other amino acids to form linear polypeptide chains that can include over a hundred amino acids. A protein can consist of a single polypeptide or can be more complex with several different polypeptides.

• The secondary structure refers to interactions between amino acids in the polypeptide chain form conformations such as alpha helices, beta strands and beta sheets (pleated sheet). These conformations are stabilised by non-covalent hydrogen bonds between amide hydrogens and carbonyl oxygens in the amino acid backbone. These structures and their formation are summarised in Figure 2.

• The tertiary structure occurs when the secondary structure elements fold and compact. This structure is stabilised via the non-covalent interactions of amino acids with its surrounding environment, amino acids that are far apart in the primary structure can be brought into close proximity.

• Some proteins have a quaternary structure, which results through the interactions of two or more of the same polypeptide or different polypeptide chain coming together to form a multi-subunit protein.


Figure 1: The four levels of protein structure. Image sourced from the National Human Genome Research Institute (NHGRI) -


Figure 2: Structures of an alpha helix and beta sheet. (A) Ribbon diagram and a structural representations of an alpha helix. The backbone atoms (black) form a coil and the carbonyl groups (red) form hydrogen bonds with the amide groups (blue). (B) Ribbon diagram and a structural representations of a beta sheet. The carboxyl groups (red) and amide (blue) groups form hydrogen bonds between the two beta strands. The two different groups tend to have alternating patterns allowing interactions to occur. This figure is adapted from

Protein Folding

Protein folding is a rapid process determined by the primary structure of the protein. Protein folding depends on the non-covalent interactions between amino acids. Non-covalent interactions tend to be weak on their own but combined they stabilise the protein structure. Types of non-covalent interactions include:

• Hydrogen bonding – as described before these tend to occur between amino acids in the polypeptide chain.

• The hydrophobic effect – water interacts preferentially with itself than with hydrophobic residues of the protein. Therefore, proteins are stabilised by forcing hydrophobic residues inside the protein and excluding water which provides energy to drive protein folding and stability.

• Van der Waals forces - contacts between non-polar side chains, make a significant contribution to protein folding and stability as non-polar side chains tend to pack densely within the interior of a protein.

• Charge-charge interactions – interaction between oppositely charged side chains, these tend to be on the surface of the protein exposed to water. Some oppositely charged ions form an ion pair within the protein and tend to be stronger than those on the surface.

Protein Examples

There are many proteins with humans having over 30, 000 different proteins. Protein can be enzymes, membrane proteins, structural proteins etc. each having a distinct function. Protein function depends on their amino acid composition and its three-dimensional structure. A few examples of proteins are discussed below.

• Haemoglobin

Haemoglobin is the one of the earliest recognised protein in its role in oxygen uptake and transport around the body in red blood cells. Haemoglobin is a tetrameric water soluble globular protein, made up of two α and β subunits, as shown in Figure 3. Each monomer in the protein contains a haem group which consists of an iron atom. The uptake of oxygen by the haemoglobin depends on the ability of the iron molecule to combine reversibly with oxygen. Haemoglobin co-operative binding, once oxygen binds to one monomer it causes a small conformational change which transmits across the three other subunits in the tetramer, which locks the other subunits in an active state. The four protein subunits interact and stabilise one another through hydrogen bonding, as well as the hydrophobic effect. 

Figure 3: The structure of haemoglobin. Image sourced from -

• Glucokinase

An example is the glycolytic enzyme hexokinase, which catalyses the first step of glycolysis which involves the phosphorylation of glucose using ATP. Hexokinase has two different conformations; in the absence of glucose it is present in an open form, whereas in the presence of glucose it exists in a closed form. The enzyme active site contains hydrophilic amino acid side chains surround the bound glucose molecule to form a widespread network of hydrogen bonds.

Figure 4: Hexokinase in open and closed form - image sourced from RCSB Protein Data Bank

• Collagen

A fibrous protein which is a major part for the connective tissue, it has a multi-strand helical structure with the ability to exist in different forms and have diverse functions. Collagen fibres in tendons are stiff and provide tensile strength, whereas in the skin collagen takes the form of loosely woven fibres, allowing expansion in different directions.

Figure 5: Coloured scanning electron micrograph (SEM) of Collagen fibres. – image sourced from


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