[gmx-users] RE: free energy of binding

[Graham Smith]

> -----Original Message-----
>
> Message: 6
> Date: Tue, 20 Sep 2005 12:31:41 -0400
> From: "Tao Li" <taol at rci.rutgers.edu>
> Subject: [gmx-users] free energy of binding
>
> Hi, all,
>
> We would like to calculate the free energy of binding for two species
in water
> with Gromacs. Basically the reaction of interest is like:  A + B -->
complex,
> and we want the free energy of reaction (binding), delta G.
>
>
> We tried the LIE method first, but no good results have been yielded.
We are
> thinking of using the FEP approach, but, we are not sure on how to
perform such
> calculation.  Should I use a thermodynamic cycle like this:
>
>
> A (vacuo)  +  B (vacu0)  ---> Complex (vacu0)   delta_G1
>  |                   |                          |
>  |                   |                          |
> A (Sol)    +    B  (Sol)    ----->  complex (solvent)   delta G
>
> So, Delta G = Delta_G1 - Delta_solv(A) - Delta_solv(B) -
Delta_solv(complex)
>
> Can I get the free energy of binding directly without having to
calculation all
> these solvation energies, and the gas phase binding energies?
>

I have recently seen a paper that does exactly that:

"Calculation of absolute protein-ligand binding free energy from
computer simulations" , H.J. Woo and B. Roux, Proc Natl Acad Sci U S A.
2005 May 10;102(19):6825-30.

They calculate the FE of binding of a peptide to an SH2 domain entirely
in solution, using a series of biasing potentials to force the molecules
into bound conformations as necessary and translate them out of solution
into the binding site. This is very new though, and if you wanted to do
it in Gromacs there'd be a lot of work on methodology development.
(There are multiple stages, and Woo and Roux have used another MD
package whose name begins with C.)

Which is the best way may depend on what your two molecules are. For
smallish molecules and small conformational changes the
vacuum-to-solution FEP method is pretty tried and tested. For large
molecules, it has big problems which are mainly the result of having to
subtract the vacuum-to-solution transfer energies, which are so huge
that the final FE of binding ends up with an enormous error. Basically,
dealing with large or flexible molecules will be a major undertaking
however you tackle it, but Woo and Roux's method looks very promising to
me. 

Graham

############################################

Dr Graham R. Smith
Biosystems Informatics Institute
2nd Floor, Bioscience Centre
International Centre for Life
Times Square
Newcastle upon Tyne NE1 4EP

http://www.biiuk.com

############################################




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