Water analysis in Flare uses advanced solvation modelling to explore the distribution, stability, and energetics of water molecules within and around a protein binding site.
By applying methods such as 3D-RISM (Three-Dimensional Reference Interaction Site Model) and GIST (Grid Inhomogeneous Solvent Theory), discovery chemists can identify regions where water molecules are energetically favorable or unfavorable, and exploit this information during ligand design. These insights help chemists decide which waters may be retained, displaced, or leveraged as water-mediated interactions during lead optimization.
Water analysis in Flare will help you:
- Reveal energetically favorable (‘happy’) and unfavorable (‘unhappy’) water sites in the binding pocket
- Gain thermodynamic insight into water distribution that can guide ligand design
- Prioritise ligand modifications aimed at displacing unfavorable waters or bridging via favorable waters
- Interpret water behaviour across apo and ligand-bound structures
Two complementary approaches are available to give you added confidence in your results:
- 3D-RISM analysis, which uses utilizes the advanced inter-molecular descriptions of the Cresset XED force field or of the AMBER GAFF force field to predict water density and free energy grids around proteins and ligands, indicating where waters are energetically stable or unstable. 3D-RISM will also populate the active site with waters, with or without a ligand present.
- GIST analysis, which derives water thermodynamic properties from restrained molecular dynamics simulations, highlighting regions of high/low water stability via heat and density maps. Grand Canonical Nonequilibrium Candidate Monte Carlo (GCNCMC) sampling can be employed during the GIST equilibration stage to enhance water sampling, potentially improving accuracy of water analysis results.
Results from these analyses can be visualised directly in Flare, allowing users to interpret hydration patterns in the context of binding site topology, ligand interactions, and thermodynamic contributions. This information is particularly useful when preparing structures for docking, free energy calculations, or prioritising ligand designs that either displace unstable water molecules or exploit stable, bridging waters.
References and acknowledgements
S. Ramsey, C. Nguyen, R. Salomon-Ferrer, R. C. Walker, M. K. Gilson, T. Kurtzman, Solvation thermodynamic mapping of molecular surfaces in AmberTools: GIST, J Comput. Chem. 2016, 37(21):2029-37
T. Luchko, S. Gusarov, D. R. Roe, C. Simmerling, D. A. Case, J. Tuszynski, A. Kovalenko, Three-Dimensional Molecular Theory of Solvation Coupled with Molecular Dynamics in Amber, J. Chem. Theory Comput. 2010, 6 (3), 607–624
R. Skyner, J.L McDonagh, C.R. Groom, T. van Mourik, J. B. O. Mitchell, C. R. Groom, T. Van Mourik, A Review of Methods for the Calculation of Solution Free Energies and the Modelling of Systems in Solution, Phys. Chem. Chem. Phys. 2015, 17 (9), 6174
M. L. Samways, H. E. Bruce Macdonald, J. W. Essex, grand: A Python Module for Grand Canonical Water Sampling in OpenMM, J. Chem. Inf. Model. 2020, 60, 10, 4436-4441
O. J. Melling, M. L. Samways, Y. Ge, D. L. Mobley, J. W. Essex, Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo, J. Chem. Theory Comput. 2023, 19, 1050-1062