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

From: Braden Kelly <>
Date: Thu, 29 Nov 2018 18:35:40 +0000

I do not see why I wouldnt use linear coupling for the electrostatic part. I do this for regular classical MD free energies. The softcore LJ is the same calculation for both MM and QM/MM is it not? So in theory, so long as Amber can calculate for each lambda window the scaled coulomb contribution to potential energy for the current window, and each neighboring window(while still exploring phase space in the current given lambda), along with the LJ contribution using a softcore potential, BAR and TI should work. I guess my original question reflects this... Is amber set up to do this? From the responses I have received, it appears to be capable of doing TI and BAR provided I use a linear scaling for the coulomb and a softcore for the LJ, which is also what I would do for a classical MD free energy calculation.

>From my experience nearly all of the Free Energy of inserting a molecule into a solution, comes from the electrostatic contributions. LJ requires more windows, but contributes much less. An issue with classical FF is that aside from LJ parameters, their parameters come largely from QM calculations done on a single molecule, in the gas phase (ideal gas). The results are fit to spring constants and called a force-field. Generally charges are fixed and forced to be symmetrical. I do not see how this can be expected to be more accurate than doing QM on the molecule while it is in the liquid phase while allowing the electronic contribution to be polarized by the explicit and moving environment - unless you are using a much lower quality of QM, or you spend some extra time parameter fitting or refining the FF with a very high level of QM. I am not a FF developer and everything I have said is my interpretation of what is done, please feel free to criticize it! I prefer being corrected to being wrong...

I am interested in a method that is as accurate as possible without needing fitting to match experiment as is done with classical FF's since I am interested in molecules which do not have experimental results to fit to. This is why I am interested in QM/MM, I believe that especially if I can include the first and hopefully second, hydration spheres in the QM part of the calculation, I will get highly accurate results that are subject to computational resources(level of theory) rather than FF parameters. Perhaps I will need to also use a polarizable water model too.

The point on water models is a very good one. First I would like to get the most accurate results for given water models, and then compare which model best mimics my reality. But I must do step 1 correctly, before doing step 2.


From: Brian Radak <>
Sent: Thursday, November 29, 2018 10:18:06 AM
Subject: Re: [AMBER] QMMM free energy calculations for alchemical changes using a coupling parameter in amber 18

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 - 11:00:02 PST
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