The primary structure of a protein is simply the sequence of amino acids in a polypeptide chain, but these polypeptide chains are folded and stacked both in regular arrangements and in a seemingly random manner to form the secondary and tertiary structures of a protein. It is this chain folding that gives a protein its 3D shape and is key to the biochemical activity of the protein.
The secondary structure of a protein
In the secondary structure the polypeptide chain spontaneously folds into a number of differing spatial arrangements, the most common of which are the ⍺-helix and the β-pleated sheet.
The amino acids in an ⍺ helix spiral in a right-handed direction, with R groups pointing out of the helix and hydrogen bonds between the N-H group of one amino acid the C=O group of an amino acid four residues / monomers earlier.
The amino acids methionine, alanine, leucine, glutamate and lysine in a sequence are commonly found to favour the formation of an ⍺-helix, whilst glycine and proline are seen to disrupt the regular helical backbone structure, ending the ⍺-helix.
In a β-pleated sheet, the polypeptide chains are aligned into a sheet-like structure with hydrogen bonds forming between the N-H group of an amino acid in one chain and the C=O group of an amino acid in the neighbouring chain. The polypeptide chains can either run parallel or antiparallel to each other, and the R groups point outwards from the ‘folds’ of the pleated sheet.
Amino acids with large bulky R groups such as tryptophan, tyrosine, phenylalanine, leucine, valine and threonine tend to favour a β-sheet formation.
We can think of these secondary structures as intermediates on the way to the further folding of a protein into its final 3D structure.
The tertiary structure of a protein
The tertiary structure refers to the further folding of the polypeptide chains into a complex 3D shape which happens almost spontaneously (it is thought this is governed by amino acids with hydrophobic R groups moving to orient themselves to the inside of the protein).
The shape is held in place by numerous interactions between the R groups of amino acids in close proximity to one another.
The Nobel prize for Chemistry was awarded to David Baker, Demis Hassabis and John Jumper in 2024 for their work in cracking the mystery of how a one-dimensional string of amino acids folds innately and near-instantaneously into a complex three-dimensional shape …
Practice questions
- Proteins are polymers made from amino acids. The R groups between different amino acids can interact and help stabilise the tertiary structure of a protein. Four amino acids are shown below:
(a) Explain how the strength of the interaction between the R groups of two cysteine amino acids differs from the strength of the interaction between the R groups of serine and aspartic acid.
(b) What is the strongest type of interaction possible between the R groups of lysine and aspartic acid? Explain your answer.
- Explain, with the aid of a diagram, how the hydrogen bonds that hold together the secondary structures of a protein arise.
Answers
- (a) Disulfide bridges (-S-S-) form between the R groups of cysteine – these are covalent bonds and stronger than the hydrogen bonds that could form between the R groups of serine and aspartic acid.
(b) An ionic bond could form if the R groups in lysine and aspartic acid were ionised to -NH3+ and -COO– respectively.
- In both an ⍺-helix and a β-pleated sheet hydrogen bonds from between the 𝛅+ hydrogen bonded to the nitrogen atom in one amino acid and the lone pair of electrons on the oxygen of a carbonyl group in a different amino acid further along the polypeptide chain in the case of the ⍺-helix or on a neighbouring polypeptide chain in the case of a β-pleated sheet.
