How to Use Grid Inhomogeneous Solvation Theory (GIST)

Grid Inhomogeneous Solvation Theory (GIST) analyzes explicit-water molecular dynamics on a three-dimensional grid around a selected site. Unlike a water-density map, it reports local occupancy together with water-solute and water-water interaction energies, translational and orientational entropy terms, and water ordering. This helps researchers distinguish densely occupied water from thermodynamically stabilized water and identify hydration regions that may be useful in ligand design.

The Neurosnap service is self-contained: an Input Structure and one positioned Grid Reference Ligand define the receptor and analysis site, then the worker prepares, solvates, equilibrates, simulates, and analyzes the system without depending on a prior molecular-dynamics job. Hydration State selects an apo map that excludes the reference ligand or a holo map that includes and parameterizes it.

Upload a receptor structure and a valid three-dimensional SDF ligand already positioned in the binding site. For an apo calculation, the ligand defines the automatic analysis grid but is omitted from the simulated solute. For a holo calculation, it remains in the system and is parameterized with the fixed ligand stack. The workflow uses AMBER14SB, TIP3P water, restrained 300 K production dynamics, and cpptraj GIST so the simulation and analysis assumptions remain compatible.

Simulation Duration and Output Frames control sampling. The worker infers a rectangular grid from the positioned ligand's heavy-atom bounds, extends it by 5 A on every side, and uses a fixed 0.5 A voxel spacing. Jobs with unusually large inferred grids are rejected rather than silently analyzed at lower resolution. Ten nanoseconds or more of production sampling is recommended for interpreting maps at this spacing; the half-versus-full table is a descriptive stability diagnostic, not proof of convergence.

Interpret occupancy, energy, and entropy maps together. High density alone does not mean hydration is favorable, and GIST is a local hydration decomposition rather than an exact ligand-binding free-energy calculation. Download the OpenDX maps for VMD or PyMOL and retain the Amber topology, trajectory, checkpoint, prepared structures, and cpptraj inputs when reproducing or extending the analysis.

• No upstream-job dependency: Preparation, explicit-water simulation, and GIST analysis run inside one service.
• Compatible fixed stack: AMBER14SB, GAFF2 for holo ligands, TIP3P, OpenMM, and cpptraj are kept in one versioned runtime.
• Ligand-defined apo or holo maps: One positioned reference ligand defines the automatic analysis region while the user chooses whether it remains in the simulated solute.
• Interpretation-ready artifacts: Human-readable voxel and diagnostic tables accompany raw OpenDX grids, trajectory, topology, checkpoint, and cpptraj provenance files.