Aimed at: Anyone interested in predicting whether water molecules in binding sites should be targeted for displacement.
Requirements: Basic knowledge of the Linux command line and basic knowledge of Python.
Abstract: Recent years have witnessed the maturation of our understanding of water in biomolecular association, such that present day structure-based drug design efforts often consider the influence of water on the ligand and protein. A typical concern is whether water molecules within binding sites should be targeted for displacement to improve affinity and specificity. The difficulty of this problem is often compounded by the existence of networks of interdependent waters.
This problem can be directly addressed through our recently developed simulation technique called Grand Canonical Integration (GCI). Simulations in the Grand Canonical ensemble are able to change particle number, providing a direct route to vary the number of waters in buried protein binding sites that circumvent sampling problems in conventional calculations. GCI provides a theoretically rigorous result to translate Grand Canonical simulation data into binding free energies, not just for individual waters but also entire networks.
In this workshop we will present the theoretical basis for GCI and demonstrate its practical application to a protein-ligand system. This workshop employs ProtoMS, the user-friendly Monte Carlo package developed by the Essex group at the University of Southampton.