From: Jason Swails <>
Date: Tue, 24 May 2016 11:57:04 -0400

On Tue, May 24, 2016 at 9:15 AM, Lara rajam <> wrote:

> Dear Amber !
> I need a suggestion regarding MMPBSA calculation.
> I have done a simulation of a protein with two ligands, bound in different
> places.
> I am able to calculate the total free energy with respect to both.
> How one know their individual total binding free energy contribution

​Such quantities are not well-defined. For instance, the binding affinity
of one ligand may be affected by the presence of the other (and vice
versa). This is allostery. Note that many examples of allostery involve
the binding of one ligand affecting the dynamics and conformational
equilibria of the complex, which in turn affects the shape and properties
of other binding sites. MM/PBSA analyses (particularly those based on
single-trajectory approaches) are poorly equipped to capture these effects.

You will need to carefully define exactly what you want to compute and
design a calculation to compute that quantity. A thorough understanding of
the MM/PBSA method -- such as the understanding you gain by running some of
these calculations "by hand" (i.e., without the use of either of the MMPBSA
scripts) -- will help you decide whether or not the approximations made
will end up invalidating your results.

So the answer to your question, as with many, many other questions that get
asked, is "it depends on what you are trying to learn".

It helps to draw the thermodynamic cycles associated with various MM/PBSA
calculations to help you decide what calculations you need to run.


Jason M. Swails
AMBER mailing list
Received on Tue May 24 2016 - 09:00:02 PDT
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