Discovery of a hidden transient state in all bromodomain families
Lluı́s Raich, Katharina Meier, Judith Günther, Clara D. Christ, Frank Noé, Simon Olsson
Abstract
Significance Proteins dynamically shape shift, adopting different three-dimensional structures, called conformations. The conformations fulfill different functions and expose different binding surfaces to drug molecules aiming to inhibit the protein. While structural biology experiments can capture the most frequently occurring conformations, those that are more rarely visited are very difficult to capture but may be functionally important. Using extensive computer simulations, we discover an undocumented conformation present in all families of bromodomains—protein domains crucial for epigenetic regulation and associated with several diseases. We also show that available experimental data confirms the existence of this previously overlooked state. The surprising ubiquity of this new conformation makes it a likely player in biological function and opens up new drug development strategies.