Buried water molecules can play a critical role in drug discovery, given that their displacement is typically associated with a favourable release of entropy (at an enthalpic cost). However, there are some limitations regarding the locations of water molecules and their effects on the protein-ligand structure. Water locations can be problematic for experimental methods, and conventional computer simulations can be significantly limited by the long timescales on which waters can exchange between binding sites and bulk solvent.

Grand canonical Monte Carlo (GCMC) is a rigorous simulation technique which bypasses these kinetic barriers to the binding and unbinding of water molecules, by introducing particle insertion and deletion moves. GCMC can be combined with molecular dynamics (MD) to allow improved water sampling on top of MD sampling of the protein-ligand complex.

My project is primarily focused on the development and enhancement of grand canonical methods (via the grand module), but also includes application projects, where we use GCMC/MD simulations to gain insights into the role of water molecules in interesting protein systems.