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

From: Brian Radak <>
Date: Thu, 29 Nov 2018 10:18:06 -0500

If you are doing TI with linear coupling then the data output is identical
to what would be needed for BAR/MBAR.

Convergence for pure QM/MM transformations would almost certainly have to
be worse unless the conformations and/or charge distributions of the MM
endpoints were substantially different. MM also has the distinct advantage
of being cleanly additive for staged decoupling.

The other question is whether or not QM/MM solvation models are even more
accurate then MM solvation models. The former certainly were never
calibrated to match experiment in any way. If anything, I would *expect*
them to be less quantitatively accurate. There have also been questions for
about 10-15 years now as to whether TIP3P or TIP4P models are "good"
solvation models (they make good pure liquid models, but that's not at all
the same thing). Why would a more accurate (really, just "higher level")
electrostatic representation suddenly improve things? It was flawed in some
specific ways (see the erratum), but I would recommend reading David
Mobley's comprehensive study of charge and solvent models for solvation
free energies (one of the JPCs I think?).


On Wed, Nov 28, 2018 at 4:15 PM Braden Kelly <> wrote:

> 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.
> Thanks,
> Braden
> ________________________________
> 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
> >QM/MM.
> 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
> something).
> 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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Received on Thu Nov 29 2018 - 07:30:02 PST
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