MRC Human Genetics Unit
Medical Research Council Human Genetics Unit

Protein complex evolution influenced by ligand binding site structure

Different types of ligand binding site affect the way that protein complexes have evolved: April 2018

Joe Marsh, Chancellor’s Fellow, MRC Human Genetics Unit

Many features of the genome change with the size of the genome, which ranges from very small in bacteria, to very large in higher organisms such as mammals. Features that generally change with genome size include the proportion of DNA that does not code for proteins, the size of introns, the rate of reshuffling of DNA within a genome (recombination), cell volume, or the mutation rate. Scientists believe this is due to different forces of selection in different sized genomes.  An exception to this appears to be the evolution of protein complexes – which are structures formed from multiple identical, or different proteins. These do not change as much as expected with different genome sizes, leading some scientists to suggest that random changes, rather than selection, may play a major role in the evolution of protein complexes.

György Abrusán and Joe Marsh at the MRC Human Genetics Unit have explored this hypothesis by examining changes in the part of protein complexes that can bind external molecules (ligands), such as metals, or drugs. If these sites change, this can alter the function of the protein complex, which could give a survival advantage to the cell or organism, and therefore impact evolution.

Using computational methods that explore information about ligand binding, the team found that several factors affected how protein complexes evolved. These included whether the protein complex bound a metal or cofactor, rather than another type of molecule, and whether the ligand-binding part of the protein complex was made up of a single protein chain or multiple chains of protein. Binding sites made from multiple chains of protein appear to evolve more slowly, thus their functions are more conserved than the functions of binding sites restricted to a single protein chain.

Understanding the differences between these types of protein complex is important for rational drug design; for example whether an antibiotic would work against many species of bacteria, or just few, or how easy it would be for bacteria to evolve resistance to an antibiotic. One implication of these findings is that it would be harder for bacteria to evolve resistance to a drug which targets a binding site made from multiple chains of protein.



  • Abrusán G, Marsh, JA. Ligand (2018) Binding Site Structure Influences the Evolution of Protein Complex Function and Topology. Cell Reports 22: 3265–3276