(Note: These tutorials are meant to provide illustrative examples of how to use the AMBER software suite to carry out simulations that can be run on a simple workstation in a reasonable period of time. They do not necessarily provide the optimal choice of parameters or methods for the particular application area.)
Copyright Ross Walker 2015

AMBER Advanced Tutorial 25
Introduction

GIST Analysis Example
Analysis of water thermodynamics using Grid Inhomogeneous Solvation Theory of Factor Xa active site.

By Romelia Salomon, Crystal Nguyen, Steven Ramsey, Jonathan D. Gough, & Ross Walker

In this tutorial we will learn how to use the AMBER software coupled with the Grid Inhomogeneous Solvation Theory Method (GIST) of Nguyen, et.al. [Crystal Nguyen, Michael K. Gilson, and Tom Young, arXiv:1108.4876v1 (2011) and Crystal N. Nguyen, Tom Kurtzman Young, and Michael K. Gilson, J. Chem. Phys. 137, 044101 (2012)] to estimate thermodynamic values for the water molecules occupying the binding pocket of Factor Xa. Often one might want to estimate changes in hydration which are central to correctly describe biomolecular phenomena such as molecular recognition, drug binding, etc. However it is difficult to estimate precisely the thermodynamic solvation contribution in these phenomena.

GIST, an analysis tool by Nguyen et al., calculates thermodynamic values of solvent located within a defined region using the grid discretized inhomogeneous solvation theory formulation. The energy of each voxel represents the full interaction between the water molecules located in that voxels with the host (usually a protein) and the other waters in the system. This energy is considered in a full way, ie, the interaction between a water molecule and any other molecule is not divided by two, and is assigned in its totality to the grid box where the water being studied resides.

WHAT CAN GIST DO: GIST is a very powerful tool that produces quantitative thermodynamic data for each grid box, or voxel. GIST allows the user to characterize each spatial position with respect to its water occupancy, the energetic interaction with other water positions and the protein, and its entropic contribution. This information can be used to decide whether the water at a given location is favorable or not compared to the bulk distribution. The following figure shows the interaction energy contour of a miniature receptor, cucurbit[7]uril, with its surrounding water. The figure shows two favorable water-host energy contours: -8.5 kcal/mol/water in orange and -4.0 kcal/mol/water in blue. The orange contour highlights the more favorable water interaction of the water and carbonyl groups of the host molecule.

The present implementation computes the long range interactions only for the central image, i.e. no periodic copies are considered and no long range methods such as PME are applied. The same is considered to estimate the bulk reference energies. All our thermodynamic calculations are done with respect to the bulk properties. At this time, the implementation of GIST in cpptraj supports the following water models:

a) TIP3P

b) TIP4P

c) TIP4PEW

d) TIP5P

e) TIP3PFW (flexible water model)

f) SPCE

g) SPCFW (flexible water model)

In this tutorial we shall use GIST to study the thermodynamic contributions to hydration in the active site of Factor Xa. (The colored axes show the left edges of the grid used to define GIST active space for this calculation, we have placed a ligand in the pocket for visual aid.)

This tutorial consists of three sections:

1) section1.htm : Creating the initial structure and relaxing it.

2) section2.htm : Running the MD calculations in Amber.

3) section3.htm : Use GIST in cpptraj to estimate thermodynamic values of hydration.

4) section4.htm : Analysis of water characteristics through GistPP application to GIST output files


CLICK HERE TO GO TO SECTION 1


(Note: These tutorials are meant to provide illustrative examples of how to use the AMBER software suite to carry out simulations that can be run on a simple workstation in a reasonable period of time. They do not necessarily provide the optimal choice of parameters or methods for the particular application area.)
Copyright Ross Walker 2015