FEP with fixed explicit environment?

From: Sebastian Stolzenberg (s.stolzenberg_at_gmail.com)
Date: Sun Mar 15 2009 - 12:03:28 CDT

there seem to be trouble with posting this email here:

Sebastian Stolzenberg wrote:
> Hi Chris,
>
> thanks for your quick reply.
>
> There is another problem I see:
> Simply fixing the environment will give me RATTLE violations, so I
> guess I first need to impose weak constraints that I gradually turn
> into a fixation.
> I see no way to calculate the free energy difference for this
> transformation, or is there any?
>
> Cheers,
> 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>
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>>>
>>> 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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