Calculating Free Energy Change by Displacing Water Molecules

Post date: Jan 6, 2020 8:10:32 PM by Joe Wu

While it is most common to consider direct ligand-protein interactions, recent research tries to consider also the solvation effect of water displacement in the binding region. Our protein of choice for this project is the bromodomain of “Pleckstrin homology domain interacting protein” (PHIP)3, a small protein module that recognizes acetylated lysines on histones and serves as an important role in the study of regulation of gene expression.1 We have chosen to study the mediation effects of the specific W1 water molecule located within the bromodomain binding region. By displacing this W1 water molecule from neat water and the bromodomain active site with a bubble potential, we were able to calculate the free energy penalty, and as such, understand the amount of net work necessary to introduce a ligand into the site. The resulting free energy change of displacing W1 in neat water was 1.3 kcal mol-1, while for the bromodomain binding pocket, this value was 0.384 kcal mol-1. To understand more extensively the energetic effects of water molecules on pocket stability and ligand binding affinity, further studies using additional water molecules can be considered.

Figure 1. Spherical bubble (translucent) in bromodomain binding pocket surrounded by water.