Re: FEP with fixed explicit environment?

From: Sebastian Stolzenberg (s.stolzenberg_at_gmail.com)
Date: Tue Mar 17 2009 - 13:21:12 CDT

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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