AMBER Archive (2005)

Subject: Re: AMBER: Re: TI tutorial

From: David A. Case (case_at_scripps.edu)
Date: Tue Jun 28 2005 - 20:09:44 CDT

On Wed, Jun 29, 2005, Jiten wrote:
>
>
> I have two protein systems bound with the same drug molecule. In one
> position at the active site of the protein ALA --> GLY are mutated which
> makes a free energy loss for ~ 1 kcal/mole.

I am assuming(?) that you mean the binding free energy for the ligand is 1
kcal/mol greater or smaller, depending on ALA vs. GLY. If you mean something
else, please disgregard the rest of this message.

> I wish to find out this
> difference using the TI calculations.

To get relative free energies of binding, you would need to convert ALA->GLY
in the presence of the ligand, and in its absence. This would involve
changing both the charges and the vdW parameters.

If you want absolute binding energies for both complexes, you would need to do
four free energy calculations (ALA -> nothing with lignad, ALA-> nothing
without ligand, GLY->nothing with ligand, GLY->nothing without ligand.) Each
of these four simulations would in turn probably be divided into electrostatic
and van der Waals contributions.

Keep in mind that 1kcal/mol is a pretty small number.

> (This will need me to have frcmod.DH file for the drug molecule ?)

I don't see how you can perfrom any calculations relevant to drug binding
without having a force field to represent the drug....

...dac

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