In living organisms, hundreds of DNA-binding proteins carry out a plethora of roles in homeostasis, transcriptional regulation in response to stress, and in maintenance and transmission of genetic information.
These DNA-binding proteins do so faithfully due to their distinct DNA-binding specificity towards their cognate DNA sites. Yet it remains unclear how related proteins, sometimes with a very similar DNA-recognition motif, can recognise entirely different DNA sites.
What were the changes at the molecular level that brought about the diversification in DNA-binding specificity?
As proteins evolved, did the intermediates in this process drastically switch DNA-binding specificity or did they transit gradually through promiscuous states that recognised multiple DNA sequences?
To investigate this the Tung Le group use evolutionary-related DNA-binding proteins (that are important for bacterial chromosome maintenance) as model systems.
They employ X-ray crystallography, molecular dynamics simulations, and deep-sequencing techniques to characterise in-depth protein-DNA interfaces of interest.
The group’s goal is to identify common biophysical mechanisms that underlie specific/promiscuous DNA recognition, and thereby understand biophysical requirements/constraints to evolve a new DNA-binding specificity. The methodologies and concepts that they develop might be applicable to studying the evolutions of other DNA-binding protein families or protein-protein interfaces.