multiple FEP experiments in one NAMD-FEP run?

From: Sebastian Stolzenberg (s.stolzenberg_at_gmail.com)
Date: Tue Mar 17 2009 - 15:51:14 CDT

Thanks so much, Peter,

let's forget about the fixed environment then.

What about doing several monomeric FEP experiments in one oligomeric
run? I can argue that the monomers don't talk to one another, but
stabilize each other structurally.

My idea is to produce one complete oligomeric FEP run, such that
\delta_G_oligomer=sum over all \delta_G_monomer values

To dissect the several free energy differences from one another, I would
post-analyze the FEP trajectories (collecting Hamiltonian values of each
monomer-system to get PMFs). The advantage is that I can start the runs
now, and meanwhile learn how to do the post-analysis.

I already checked the separation of the multiple FEP mutation sites: in
VMD, displaying atoms "within $R" Angstrom around each FEP site, the
resulting "blobs" only start to overlap at $R~19A.

In principle, is *this* reasonable? ... feasible with NAMD-FEP?

Thank you again,
Sebastian

Peter Freddolino wrote:
> 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.
>
> Best,
> Peter
>
>
> 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
>>>>>
>>>>> char_at_ks.uiuc.edu Voice: 217-244-1733
>>>>> http://www.ks.uiuc.edu/~char Fax: 217-244-6078
>>>>>
>>>>>
>>>>> Sebastian Stolzenberg <s.stolzenberg_at_gmail.com> writes:
>>>>>
>>>>>
>>>>>> Date: Thu, 12 Mar 2009 19:50:32 -0400
>>>>>> From: Sebastian Stolzenberg <s.stolzenberg_at_gmail.com>
>>>>>> To: namd-l_at_ks.uiuc.edu
>>>>>> Subject: namd-l: FEP with fixed explicit environment?
>>>>>> Return-Path: char_at_halifax.ks.uiuc.edu
>>>>>> Message-ID: <49B99FC8.2080505_at_gmail.com>
>>>>>> 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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