Re: DOF during alchemical simulations

From: Grace Brannigan (
Date: Mon Nov 30 2015 - 12:05:36 CST

Hi Brian,

Yes, I think it makes sense that alchDecouple on/off should affect this
error, but I can't tell if it's in the way you're thinking.

With alchDecouple on, the translational and intramolecular dof of the
decoupled molecule should be preserved - so I wouldn't think there would be
any dof-associated error.

I'm not sure how the periodic images are relevant to calculating the dof -
it may be useful here to view them as just changing the potential energy.
The 'ideal gas' or translational contribution of the decoupled molecule to
the pressure is determined by the bounds on xyz, which is independent of
whether pbc is used, and shouldn't change much over decoupling.

For alchDecouple off I think things get more complicated, but primarily due
to a change in intramolecular dof - which would probably be trickier to
correct for in a general way. The error in the estimated pressure should
become negligible for n << N, so it could be an issue if a
double-annihilation thermodynamic cycle had two FEP calculations with
really different N.


On Mon, Nov 30, 2015 at 10:36 AM, Brian Radak <> wrote:

> I'm glad this is intriguing rather than a non-issue. I agree that whatever
> systematic errors are present are likely quite negligible. Nonetheless,
> they can still be discerned from simple tests and I dislike being incorrect
> when the right answer can be easily achieved.
> My thought was that the degrees of freedom ought to depend on the
> decoupling scheme (alchdecouple on/of), as this determines whether or not
> the annihilated atoms see their images (exist as a periodic "gas") or not
> (are an ideal gas molecule). Does it make sense for ideal gas degrees of
> freedom to impact the pressure? My first thought would be that they should
> not impact sampling at all; I believe manipulations with ideal gas
> partition functions ought to confirm this is true.
> Would it make sense to have different behavior when alchDecouple is on or
> off? This would only meaningfully differ at alchLambda = 0,1, as the
> intervening values are totally arbitrary, so long as sampling is not
> grossly impacted.
> Brian
> On 11/27/2015 03:31 AM, Jérôme Hénin wrote:
> On 26 November 2015 at 19:28, Aron Broom <> wrote:
>> This is really interesting. My knowledge of alchemical transformations
>> in limited, but given their successes I'd like to understand more (and will
>> happily be corrected on my errors in thinking).
>> If you leave those degrees of freedom in, then the end-point simulations
>> are actually different than a similar simulation of that system where you
>> aren't doing an alchemical transformation. That raises for me a kind of
>> intuitive red-flag, which I think is the same point you are making?
> I agree with you on this. This is among the terms that we neglect when
> doing alchemical calculations in an isobaric simulations. If you decouple n
> particles among N and have a barostat set at pressure P0, you will generate
> an ensemble for the (N-n) particles at pressure P = P0 - Pn, where Pn is
> the kinetic pressure from just n particles at the given volume and
> temperature. If I get my orders of magnitude right: decoupling one particle
> in a thousand from a condensed phase will underestimate the pressure by (on
> the order of) 1 bar. That's something I can live with: I can say worse
> things about my simulations.
>> But on the other hand, if at the end-points you suddenly eliminate those
>> degrees of freedom completely, doesn't that create a discontinuity in the
>> transformation, which is a bad thing and source of much misery?
> Unless you do TI, it's not a problem in and of itself: other estimators
> explicitly give FE differences between discrete states. The tricky part may
> be to account for that explicitly in the free energy estimator.
> Probably an idiotic question from someone with limited physics
>> understanding, but I suppose non-integer degrees of freedom are disallowed
>> (assuming similar fractional counting of mass and velocity)?
> Nothing prevents us from using a fractional number when calculating
> kinetic pressure, although it doesn't have much physical meaning. That's
> pretty much the spirit of alchemical transformations. Again, I'd be totally
> happy with it if the estimators were rewritten with that in mind.
> Jerome
>> On Thu, Nov 26, 2015 at 1:00 PM, Jérôme Hénin < <>
>>> wrote:
>>> Brian,
>>> I might be missing something, but I'd say the degrees of freedom of
>>> non-interacting particles should be counted for the purpose of kinetic
>>> pressure calculation.
>>> Jerome
>>> On 25 November 2015 at 17:31, Brian Radak < <>
>>>> wrote:
>>>> After some griping about this, I've finally implemented a (preliminary)
>>>> correction to the Lennard-Jones tail correction that accounts for
>>>> alchemical modifications. Once this is integrated with other improvements
>>>> to the alchemical code, I hope this will become part of the 2.11 release.
>>>> However, I recently noticed that a similar problem crops up in the
>>>> degrees of freedom calculation. That is, alchemical atoms get counted at
>>>> the endpoints even when they are only ideal gas particles. This was obvious
>>>> when I started double checking single coordinate endpoint energies and
>>>> pressures with dual coordinate alchemical energies and pressures; that is,
>>>> the energies match but the pressures do not quite match.
>>>> The error is admittedly much less than 0.1%, as multiplying a "more
>>>> different" large number by a small number is still just another "kind of
>>>> large" number. Nonetheless, one could view this as an error in the
>>>> specified target pressure for an alchemical simulation (i.e. the pressure
>>>> you input is not the pressure you simulate). Then again, this behavior
>>>> might be exactly what one is expecting, depending on how one draws the
>>>> thermodynamic cycle.
>>>> I guess my question for the community is, does this matter? How do
>>>> people expect degrees of freedom to be determined? Do people usually draw
>>>> their cycles such that non-interacting particles should not contribute?
>>>> This might not be the case, for example, in ligand binding calculations
>>>> where the ligand continues to interact with its own images (although in
>>>> that case, one essentially has two simulations going at the same time when
>>>> the ligand is decoupled).
>>>> Brian
>>>> --
>>>> Brian Radak
>>>> Theta Early Science Program Postdoctoral Appointee
>>>> Leadership Computing Facility
>>>> Argonne National Laboratory
>>>> 9700 South Cass Avenue
>>>> Building 240, 1.D.16
>>>> Lemont, IL 60439-4871
>>>> Tel: 630/252-8643
>>>> email:
>> --
>> Aron Broom M.Sc
>> PhD Student
>> Department of Chemistry
>> University of Waterloo
> --
> Brian Radak
> Theta Early Science Program Postdoctoral Appointee
> Leadership Computing Facility
> Argonne National Laboratory
> 9700 South Cass Avenue
> Building 240, 1.D.16
> Lemont, IL 60439-4871
> Tel: 630/252-8643
> email:

Grace Brannigan, Ph.D.
Assistant Professor
Center for Computational and Integrative Biology (CCIB) &
Department of Physics
Rutgers University, Camden, NJ

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