Re: [AMBER] QMMM free energy calculations for alchemical changes using a coupling parameter in amber 18

From: Braden Kelly <>
Date: Wed, 28 Nov 2018 21:15:14 +0000

Thanks to both David and Brian for answering my question.

I will give TI a shot and be careful. I won't know if semi-empirical will work for my system until I try it. I have just had little to no luck finding a software that would let me try it.

I used to be very excited about the end state correction QM/MM since FEP is always a little bit exciting, however am a little more guarded now. Sampling and convergence is an issue, and there are cases where the QM/MM correction made the result deviate further from experiment than the original MD free energy. From what I can tell, it is completely doable using Amber, and conveniently, Amber looks like it also takes care of the QM reference state conversion. So with a bit of python or bash post process scripting, amber should work well for this option.

I look forward to when Amber and other software can do double sided alchemical changes (BAR/MBAR) using QM/MM.

Explicit methods for calculating chemical potentials, which can then be used in a classical thermodynamic framework to predict nearly anything of chemical use, are my preferred choice, but I should explore all options, and will take a deeper look into implicit solvent models.



From: David Case <>
Sent: Tuesday, November 27, 2018 9:51:46 PM
To: AMBER Mailing List
Subject: Re: [AMBER] QMMM free energy calculations for alchemical changes using a coupling parameter in amber 18

On Tue, Nov 27, 2018, Braden Kelly wrote:
>Amber documentation covers Free Energy calculations, such as
>thermodynamic integration and using other methods such as BAR. It
>independently discusses QM/MM as well. However free energy calculations,
>specifically alchemical changes in which a molecule is decoupled from the
>system, or mutated into another molecule, using a lambda parameter that
>changes from 0 to 1 or vice versa, are not discussed in the context of

In sander, one *can* put TI and QM/MM together; special care would need to
be taken with softcore LJ terms (and use of softcore electrostatics would
not work at all.) I don't see any way to use BAR (but I might be missing

The downside is that one needs to be able to afford the QM/MM
calculation in the first place, and to carry out significant simulations
at a variety of lambda points. This requires a *lot* of computation,
unless you happen to have a system where semiempirical or DFTB
Hamiltonians are accurate enough for your purposes.

It is for this reason that a big portion of current research in this
area explores the suggestion made by Brian: carry out a transformation
at the MM level, then apply MM->QM/MM "corrections" at the end points.
In favorable circumstances, this can involve many fewer QM calculations,
which generally are by far the most expensive parts of the simulation.

>I am specifically interested in hydration free energies of small (<50
>atoms) organic molecules.

If you want just the hydration free energies, you might be better off
which implicit solvent models, such as the various flavors of
"Minnesota" models (such as SMx and its many variants.) Using explicit
solvent models (and a program like Amber) would mainly be of interest if
you want the difference in solvation energy between two environments,
say pure water, and a protein/water environment.

....good luck....dac

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