Understanding the location and energetics of water molecules is helpful for rational drug design. We present our grand canonical Monte Carlo (GCMC) method for predicting water locations and binding free energies in proteins. Further, we can calculate binding free energies of ligands with different active-site water networks by combining ligand alchemical perturbations and GCMC in a single simulation (GCAP).<br/><br/>The energetics of an active site water molecule can be vital to drug binding, through either stabilising the bound complex, or releasing entropy upon water displacement. Rationalising how water molecules should be treated is difficult – whether a water molecule should be retained in a bound structure, or if it should be displaced to recover entropy and allow for direct protein-ligand interactions, is unclear. GCMC is able to calculate the free energy of multiple water networks in a single simulation, and as the water location is predicted automatically as part of the simulation, no experimental knowledge of hydration site location is required.<br/><br/>While it is important to understand the hydration thermodynamics in protein systems, the most important property remains the ligand binding free energy. Although conventional free energy simulations can calculate relative binding free energies of ligands, issues can arise when the water network changes with the ligand. We show that GCMC can now be performed in conjunction with ligand binding free energy simulations, using our method - GCAP. This allows for direct calculation of relative free energies between ligands with different water occupancies within a single simulation. This will be demonstrated with example systems Scytalone Dehydratase and OppA. GCAP is therefore able to directly provide the free energy difference between ligands while automatically accounting for changing hydration effects.

Predicting water networks and ligand binding free energies in proteins using grand canonical Monte Carlo

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.