Re: Alchemical transformations and DDG of point mutations

From: JC Gumbart (gumbart_at_ks.uiuc.edu)
Date: Thu Dec 13 2012 - 15:47:14 CST

> This is irrelevant, because Mutator plus Alchemify make sure that
> the correct exclusion list is established so that the end states of your
> alchemical transformation never see each other.

This is outdated - recent versions of NAMD (for at least the last couple years?) automatically generates the exclusions without the need to add them to the psf. I don't believe there's any need for Alchemify anymore.

On Dec 13, 2012, at 12:47 PM, Chris Chipot wrote:

> Gianluca,
>> 1) Is it better to use alchemy in NAMD in the FEP or TI mode for this type of calculatons?
> Contrary to several extraordinary claims (which have never been
> supported by extraordinary evidences), there is no real advantage
> to use TI over FEP, or the other way around. I would, nonetheless,
> advocate FEP for practical reasons -- you can subsequently use
> parseFEP for your post-analysis, notably get the BAR estimator.
>> 2) You describe that in each FEP calculation, 30 intermediate states were considered. Does this mean that the progress of lambda was broken down into 30 windows each of 150+150 ps? How many FEP simulations did you run in total?
> Yes to the first question. I do not quite get the second -- the windows
> are chained and the net free-energy change is the sum of free-energy
> changes in individual strata.
>> 3) Do I need to use AlchDecouple on or off?
> I strongly advocate AlchDecouple off, in particular for solvation
> free-energy calculations, as one simply cannot assume that the
> conformational ensembles in vacuum and in condensed phase
> are identical.
>> 4) The VMD mutator plugin replaces both the wild-type and mutant side chains such that both clash with the backbone. If this is a problem, I might create the PDB myself and still use the PSF generated with VMD.
> This is irrelevant, because Mutator plus Alchemify make sure that
> the correct exclusion list is established so that the end states of your
> alchemical transformation never see each other.
>> Sorry, lots of questions. I would appreciate any help on this!
> Hopefully, I was convincing enough that it will stop here!
>
>
> Chris Chipot
>
> --
> _______________________________________________________________________
>
> Chris Chipot, Ph.D.
> Theoretical and Computational Biophysics Group
> Beckman Institute
> University of Illinois at Urbana-Champaign
> 405 North Mathews Phone: (217) 244-5711
> Urbana, Illinois 61801 Fax: (217) 244-6078
>
> E-mail: chipot_at_ks.uiuc.edu
> Christophe.Chipot_at_edam.uhp-nancy.fr
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> http://www.edam.uhp-nancy.fr
>
> The light shines in the darkness, and the darkness has not overcome it.
> John 1:5.
> _______________________________________________________________________

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