Effects on core protein structures

An important factor in the effect of variation on protein structure is in the packing of the amino acids in the core of the protein structure.

Most protein side chains are designated as either hydrophilic residues or hydrophobic residues. For a soluble protein, the outer surface of the protein is mainly composed of hydrophilic residues, whereas the core of the protein involves the packing of hydrophobic residues, away from the water in the solution.

A variant that involves a change in the protein core from a hydrophobic residue to a hydrophilic one may destabilise the protein enough for function to be lost. Because the protein core is tightly packed, a change from a small amino acid (e.g. alanine) to a bulkier one (e.g. phenylalanine) may not be accommodated and may lead to the protein being unable to fold into its 3D form.

An example of hydrophobic to hydrophilic variation is in human cystatin where a single variant, Leucine (L) to Glutamine (Q), destabilises the core of the protein. This variant, found to be more predominant in the Icelandic population, causes a large scale structural change leading to amyloid formation and cerebral haemorrhage (Figure 8).