Optimising small molecule binding through water networks

When small molecules bind to proteins they perturb a network of water molecules present in the unbound state of the protein. For example, some water molecules will be replaced, others will engage in interactions with the small molecule. This perturbance of the water network fundamentally affects the overall free binding energy of drug binding. Despite this fundamental effect, its contributions to and effect on the overall binding affinity of the small molecule remain incompletely understood thus limiting the predictive power of structure-based design approaches e.g. when designing ligands for unoccupied pockets and apo structures.
The overall aim of this PhD project is to make contributions to the understanding of how interfering with water networks affects the thermodynamics of small molecule binding. To achieve that, we will initially select a drug / target system where the water network in the apo as well as in the ligand bound form of the protein are well characterised through high-resolution crystal structures. We will use different in silico tools to calculate the binding free energy of key water molecules both in the apo and drug bound form to assess to which extend this change in the water network affects the overall binding energy. We will complement these predictions with isothermal calorimetry (ITC) measurements to determine thermodynamic footprint of key binders. We will then combine the small molecule SAR, the predictions of the binding free energy of key water molecules, crystal structure information and the ITC measurements to propose a quantitative model of drug binding to this particular protein that includes the perturbation of the water network.