Re: [AMBER] How to calculate the free energy change of a chemical reaction by the thermodynamic integration approach?

From: Brian Radak <>
Date: Fri, 11 Oct 2013 09:30:45 -0400

Thermodynamic integration, at least in the way that the term is generally
used in the literature, is not usually used for this purpose. If you mean
to calculate the PMF along a reaction coordinate, there are a variety of
methods using constrained, biased, and adaptively biased MD that involve
integration of the force. I don't have all of the papers on hand, but you
would do well to survey the work of Darve, Pohorille, den Otter, Ciccotti,
and many others (I'm sure I have missed at least one or two significant

In any event, AMBER does not have a straightforward implementation for the
more exotic constraints that you might want nor does it have a well
supported adaptive biasing module (the NCSU modules *might* work for this).
That only leaves the "conventional" umbrella sampling route and the details
of the simulation remain unchanged except for the analysis.

I suppose it would be possible to perform a series of alchemical mutations
converting the system from a reactant state to a "transition state," but
the free energy calculated along this path via integration would be
arbitrary and therefore probably meaningless. The differences between
"physical" states might be meaningful, but I'm not sure to what extent or
under what assumptions. In any event I have never seen such an approach in
the literature.


On Fri, Oct 11, 2013 at 2:18 AM, cwt <> wrote:

> Dear all Amber users,
> I am trying to calculate the reaction mechanism of an enzyme by the
> thermodynamic integration approach with Amber package. But I notice that in
> the thermodynamic integration, one should set the starting and ending
> states to calculate the energy difference between them. Previously I use
> umbrella sampling to get the potential mean force (PMF) of a reaction. I am
> confused if I want to use thermodynamic integration approach, should I
> define many groups along the reaction coordinate of reaction path, and add
> a constraint force on the atoms of reaction? Should I combine the
> thermodynamic integration with umbrella sampling?
> Many thanks!
> Wen-Ting Chu
> _______________________________________________
> AMBER mailing list

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 Brian Radak                                             :     BioMaPS
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Received on Fri Oct 11 2013 - 07:00:04 PDT
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