FixedLigandBind

Ligand-binding into protein at fixed ligand-protein configuration

The free energy of ligand binding into protein is the difference of the solvation free energies in two systems.
One is the solvation free energy of the ligand solute in bulk water.
The other is the free energy of solvation when the ligand is viewed as the solute and the protein and water as mixed solvent.
The solvation free energy is the reversible work for introducing the solute-solvent interaction and corresponds to the free-energy change of the system for bringing the solute from vacuum.

The calculation is readily possible in the ERMOD program for the solvation free energy of the ligand solute in bulk water.
The calculation is not stable yet, however, for the solvation free energy of the ligand into the protein-water mixed solvent when the ligand and protein are treated as flexible molecules.
This situation is in contrast to the cases of the molecular binding into micelle and lipid membrane, which can be handled rather straightforwardly with the ERmod program when the molecular flexibility and the system inhomogeneity are naturally incorporated.

A workaround at the present is to fix the structures of the ligand and protein.
When their structures are fixed, only the water motion is sampled.
At a given fixed structure of ligand-protein complex, the solvation free energy is expressed as the sum of the ligand-protein interaction and the free-energy contribution from water at the fixed protein configuration.
The ligand-protein interaction is exact, and only the free-energy contribution from water is approximately treated through the free-energy functional.
A set of ligand-protein configurations can be prepared, and the solvation free energy of the ligand solute can be evaluated at each fixed ligand-protein configuration.
The average of the solvation free energies thus obtained provides the free energy of ligand binding with flexible ligand-protein configuration, which is the initial target of computation, when the correction is made for the entropy accounting for the fluctuation of the ligand-protein complex.

To compute the solvation free energy of a fixed ligand-protein configuration, a few modifications need be done for the input files to the ermod program.
Since the ligand is a rigid solute, the gen_input script is to be conducted as such.
See Quick Start Guide/NAMD, Quick Start Guide/GROMACS or Quick Start Guide/AMBER to prepare a rigid solute with gen_input.
Essentially, the rigid solute is prepared only by modifying the refs/SltInfo file.
This file can be modified manually in the format described in Parameter files for ermod.
It is enough to modify refs/SltInfo, and it is not necessary to modify soln/SltInfo.
The soln system does not care whether the solute is flexible or rigid, and the change of soln/SltInfo to incorporate the molecular structure is not effective.
There are a few more modifications needed for the parameters_er file.
It is not necessary to modify soln/parameters_er at all.
For the refs/parameters_er file, the followings are necessary;

::::text
slttype = 2
inscfg = 2
maxins = 1

slttype = 2 means that the solute is rigid.
With inscfg = 2, the insertion is carried out by using the coordinates within the SltInfo file as is.
The maxins parameter identifies the number of insertions per solvent configuration.
In the present case, the rigid solute is inserted at fixed position and orientation, and thus there is no point of inserting the solute more than once.
See Parameter files for ermod for detailed descriptions of the parameters.