Re: FEP with fixed explicit environment?

From: Peter Freddolino (
Date: Tue Mar 17 2009 - 14:10:07 CDT

Hi Sebastien,
I wouldn't worry about the "large-restraint" -> "fixed" transition; you
can calculate the free energy change for it, and it will be relatively
easy to do so because the conformations that you see are so similar. I
would be more worried about the zero restraint -> light restraint step,
for whatever the first restraint that you are using is, since to get
correct results you would have to sample a prohibitively large variety
of conformations (all populated relative interactions of the monomers in
your structure and associated conformations of the environment) in the
zero constraint state if you cannot apply some additional constraint to
the region of phase space that you are considering. See Journal of
Chemical Physics, 129, 134102 for something conceptually similar, but
note that in that reference the unrestrained endpoint is defined in a
way that vastly reduces the variety of conformations being considered.

You should also note two other things:
-the free energy changes associated with fixing the environment will be
massive compared to what you get from your FEP, and you may well not be
able to get any useful data out because the uncertainty of the
constraint free energy will be so large
-the rate-limiting step in MD calculations is usually PME, which will
not be accelerated by fixing a good chunk of the system, so your
computational savings may not be as large as you expect

Overall I would expect that while in principal you could follow the path
that you are proposing, in practice the computer time required to
calculate the free energy differences associated with applying the
constraint to a sufficient degree of accuracy will be much larger than
the savings you can expect from it, and you will in the process end up
with more statistical uncertainty in your results.


Sebastian Stolzenberg wrote:
> Dear Chris, Dear All,
> let me rephrase my question:
> I have an oligomeric structure and I can argue that FEPs on a single
> monomer have no significant conformational influence on the other
> monomers. Therefore, fixing the monomer's environment (the other
> monomers and the surrounding lipid/solvent molecules) saves me CPU time.
> This is the plan for my FEP calculation:
> a) step-wise *in*crease positional constraints on the monomer's
> environment up to a *large* constraints force constant (by manually
> calculating PMFs from the output of MD with the regular
> "constraintScaling" commands).
> b) NAMD-FEP on the monomer with *fixed* environment
> c) gradually *de*crease positional constraints on the monomer's
> environment down from a *large* constraints force constant (same way as
> in (a) )
> my question:
> I worry about the transition "large-constraints"->"fixed" environment
> for obtaining reasonable free energy difference. Are my concerns
> practically justified? If yes, how can I circumvent them to still save
> computational time?
> Thank you very much,
> Sebastian
>>> Chris Harrison wrote:
>>>> Sebastian,
>>>> Simple question first: Can NAMD do this? Yes. There's nothing in
>>>> the code that prevents it. Can't think of a reason NAMD wouldn't
>>>> execute successfully.
>>>> Hard question: Should you do this? During any alchemical
>>>> perturbation there is the possibility that the environment
>>>> dynamically responds by rearranging its conformation. If you can
>>>> justify that any changes of the conformational ensemble that occur
>>>> during a restrained R->A perturbation are not significantly
>>>> different from conformational ensemble changes that occur during an
>>>> unrestrained R->A perturbation, then you may be able to do this.
>>>> So, the atoms beyond your 30 Ang radius would have to fullfill the
>>>> criteria that the dynamics of those atoms you wish to restrain do
>>>> not respond to the R->A perturbation and the unrestrained atoms'
>>>> dynamical response(s) to the perturbation is not altered by the
>>>> presence of the restrained atoms. Please let me know how it goes.
>>>> I'm interested to know if it works successfully {meaning a) no NAMD
>>>> crashes & b) you get a correct/reasonable result}.
>>>> C.
>>>> --
>>>> Chris Harrison, Ph.D.
>>>> Theoretical and Computational Biophysics Group
>>>> NIH Resource for Macromolecular Modeling and Bioinformatics
>>>> Beckman Institute for Advanced Science and Technology
>>>> University of Illinois, 405 N. Mathews Ave., Urbana, IL 61801
>>>> Voice: 217-244-1733
>>>> Fax: 217-244-6078
>>>> Sebastian Stolzenberg <> writes:
>>>>> Date: Thu, 12 Mar 2009 19:50:32 -0400
>>>>> From: Sebastian Stolzenberg <>
>>>>> To:
>>>>> Subject: namd-l: FEP with fixed explicit environment?
>>>>> Return-Path:
>>>>> Message-ID: <>
>>>>> X-Spam-Status: No, score=-2.2 required=5.0 tests=AWL,BAYES_00
>>>>> autolearn=unavailable version=3.1.7-0+tcb1
>>>>> Dear Everybody,
>>>>> I have an equilibrated NPT structure of a protein in explicit
>>>>> lipid/solvent with periodic boundary conditions. Let's assume I do
>>>>> a mutation R105A with dual-topology FEP. Certainly, I will also
>>>>> need to transform a bulk water molecule (WAT) into a sodium (SOD)
>>>>> to keep the net charge=0. To get the final free energy difference,
>>>>> I will subtract delta_G(WAT->SOD) that I get from a separate run.
>>>>> The system is large, I was thinking about fixing all atoms of the
>>>>> system except for the ones around ~30A of the R105A mutation and
>>>>> the WAT->SOD transformation. (Of course, I will not have a
>>>>> fixation boundary crossing covalent bonds that leads e.g. to
>>>>> RATTLE constraint violations).
>>>>> Is this feasible with NAMD-FEP? Any troubles with periodic
>>>>> boundary conditions? I know that all could be locally done with
>>>>> implicit lipid/solvent in CHARMM, which I would like to avoid for
>>>>> now.
>>>>> Thanks so much,
>>>>> Sebastian

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