# [gmx-users] PMF decompostion

Justin Lemkul jalemkul at vt.edu
Mon Dec 5 15:18:03 CET 2016


On 12/5/16 6:36 AM, Salman Zarrini wrote:
> If the force field is the issue, then, I would say the decomposition of
> free energy in the perturbation based methods like alchemical is
> meaningless as well, however, there are bunch of published works reporting
> the evolution of free energy based on their contributors coupling
> parameters, \lambda_{elec}, \lambda_{vdW} ... .
>

Perturbing the Hamiltonian as a function of lambda is more informative than what
it sounded like you were talking about.  If one wants to do, e.g. a FEP
calculation within each window and separate out various terms, that might be
useful.  Simply calculating interaction energies is not.  My main point was
cautionary - many force fields do not ascribe physical significance to the
individual contributions, and pretty much all force fields are built on the
concept of cancellation of errors.  With CHARMM, we try to get a reasonable
balance and we use free energy of hydration as target data when possible after
establishing the electrostatic parameters (charges) based on QM water
interactions.  So the balance is pretty good, in general, aside from the few
instances where NBFIX has to clean up some issues, whether they arise from the
additive functional form itself (a fundamental limitation) or the combination rules.

> No comment on desolvation energy, please?
> If the desolvation energy originated from protein-water or in my case solid
> surface-water interaction, will be taken into account automatically when
> one calculates the free energy in aqueous solution by PMF or FEP in gromacs?
>

Everything is dictated by the force field.  So naturally, any molecule-water
interaction is involved because these forces, in turn, play a role in how much
work the biasing potential has to do in each window.

-Justin

> Thanks,
>
> Salman Zarrini
>
>
> On Mon, Dec 5, 2016 at 12:07 AM, Justin Lemkul <jalemkul at vt.edu> wrote:
>
>>
>>
>> On 12/3/16 10:29 AM, Salman Zarrini wrote:
>>
>>> Thanks David and Christopher for your responses.
>>>
>>> I do not understand why vdW and Q are not meaningful contributors of PMF
>>> as
>>> a biasing method, as I think one can loop over the trajectory of all the
>>> biasing method either from US or Metadynamics and recompute the force
>>> separating vdW and electrostatic and then project them on to the reaction
>>> coordinate ... ,  after doing a little math, averaging, integration and
>>> scripting you have the portion of each energy.
>>>
>>>
>> These are force field quantities, not real physical quantities.  Depending
>> on how the force field was parametrized, decomposing the total energy may
>> be completely unphysical and therefore useless.  Sometimes inclusion of a
>> term in vdW is a compensation for inadequate electrostatic representations
>> and/or deficiencies in LJ combination rules.  Take, for a simple example,
>> NBFIX in CHARMM between ions.  There is no way to change the ion parameters
>> in the additive force field (they have to be, e.g. +1 or -1 charge), and
>> their LJ reproduce individual ion hydration free energies, so we mitigate
>> overly attractive cation-anion interactions in some cases by modifying LJ
>> specifically for their interaction while leaving ion-water interactions
>> (default combination rules) alone.
>>
>> So, sure, you can recompute and/or decompose these energies, but they
>> don't necessarily mean anything.
>>
>> -Justin
>>
>>
>> Concerning to the entropy and enthalpy portions, I am using covar and
>>> anaeig to calculate eigenvectors over "non-water" ingredients for both
>>> analyzing and fitting,  and then quasihamonic approximation and
>>> Schlitter's
>>> formula for the entropy, but the problem is that, already the difference
>>> between the entropy out of these two methods is something around "43 kcal/
>>> mol" in each windows, if this is normal?
>>> Both analyzing and fitting are "non-mass wighted" in my calculations.
>>> Do you think I should get something close to the entropy of the
>>> quasihamonic approximation Schlitter's formula if I use the method
>>> proposed
>>> by you?
>>>
>>> Cheers,
>>>
>>> Salman Zarrini
>>>
>>>
>>>
>>> On Sat, Dec 3, 2016 at 7:19 AM, David van der Spoel <spoel at xray.bmc.uu.se
>>>>
>>> wrote:
>>>
>>> On 02/12/16 23:40, Christopher Neale wrote:
>>>>
>>>> PMF gives free energy, which can not be decomposed into VDW and Q without
>>>>> leaving a remainder, though I guess that doesn't affect your question.
>>>>> Enthalpy is simply the average potential energy plus the pressure volume
>>>>> component. So you can compute average potential energy VDW and Q
>>>>> components
>>>>> at each umbrella if you want (from the .edr files with gmx energy). Be
>>>>> aware that the statistical uncertainty on the enthalpy tends to be
>>>>> greater
>>>>> than the relevant differences on achievable simulation timescales (i.e.,
>>>>> convergence is hard), so you'll want to evaluate error explicitly.
>>>>>
>>>>> Agree with Chris here, that enthalpy and entropy are the
>>>>>
>>>> thermodynamically meaningful components here. VDW and Q does not mean
>>>> anything outside the force field definition since they can not be
>>>> measured
>>>> in any way. For more info on decomposing into enthalpy and entropy, see
>>>> this paper: http://pubs.acs.org/doi/abs/10.1021/ct400404q
>>>>
>>>> ________________________________________
>>>>
>>>>> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
>>>>> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Salman
>>>>> Zarrini <salman.zarrini at gmail.com>
>>>>> Sent: 02 December 2016 17:16:15
>>>>> To: gmx-users at gromacs.org
>>>>> Subject: [gmx-users] PMF decompostion
>>>>>
>>>>> Dear gromacs user,
>>>>>
>>>>> I was wondering if something has been already implemented in gromacs to
>>>>> make possible the potential of mean force (PMF) decomposition into the
>>>>> van
>>>>> der waals and electrostatic energies?
>>>>>
>>>>> Would you please also let me know if the desolvation energy originated
>>>>> from
>>>>> protein-water or in my case solid surface-water interaction, will be
>>>>> taken
>>>>> into account automatically when one calculates the PMF in aqueous
>>>>> solution
>>>>> in gromacs?
>>>>>
>>>>> Thanks.
>>>>>
>>>>> Cheers,
>>>>> Salman Zarrini
>>>>> --
>>>>> Gromacs Users mailing list
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>>>>>
>>>>>
>>>> --
>>>> David van der Spoel, Ph.D., Professor of Biology
>>>> Dept. of Cell & Molec. Biol., Uppsala University.
>>>> Box 596, 75124 Uppsala, Sweden. Phone:  +46184714205.
>>>> spoel at xray.bmc.uu.se    http://folding.bmc.uu.se
>>>>
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>> --
>> ==================================================
>>
>> Justin A. Lemkul, Ph.D.
>> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>>
>> Department of Pharmaceutical Sciences
>> School of Pharmacy
>> Health Sciences Facility II, Room 629
>> University of Maryland, Baltimore
>> 20 Penn St.
>> Baltimore, MD 21201
>>
>> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
>> http://mackerell.umaryland.edu/~jalemkul
>>
>> ==================================================
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--
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==================================================