Re: Alchemical transformations and DDG of point mutations

From: Jérôme Hénin (jerome.henin_at_ibpc.fr)
Date: Mon Dec 17 2012 - 03:06:19 CST

Oh, I thought that bug was actually fixed at some point, but it could have been after 2.9 was released.

Jerome

----- Original Message -----
> This is not a exactly a problem with the exclusions. The problem is
> that NAMD looks for parameters BEFORE auto-generating the
> exclusions. So it tries to find a parameter that it will never
> need, and then complains when it can't.
>
> I raised this issue a couple years ago, but I guess it never got
> fixed.
>
>
> On Dec 14, 2012, at 7:07 PM, Gianluca Interlandi wrote:
>
> > I found that I DO need to use alchemify explicitly if I use psfgen
> > instead of the mutator plugin. I am using NAMD2.9 and during
> > minimization it complained of not funding angle parameters for
> > CBA-CA-CBB. This is because the PSF generated by psfgen included
> > that angle. So, I ran alchemify on it and minimization is running
> > fine now.
> >
> > The alchemify website says
> > (http://www.edam.uhp-nancy.fr/Alchemify/):
> >
> > "As of NAMD 2.7b2, alchemify is not needed anymore, since all
> > unwanted
> > terms are discarded by NAMD at runtime."
> >
> > This does not seem to be true, at least not for minimization. Or,
> > could it be that I'm using a binary compiled with the memory
> > optimized option? How do I find that out? I'm using
> > "NAMD_2.9_Linux-x86_64".
> >
> > In any case, I ran alchemify also on the solvated and ionized
> > structure just to be sure that the nonbonded exclusion list is
> > created and taken into account.
> >
> > Thanks,
> >
> > Gianluca
> >
> > On Thu, 13 Dec 2012, JC Gumbart wrote:
> >
> >> 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 This is outdated - recent versions of NAMD (for at least the last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
> >> Web: http://www.ks.uiuc.edu/~chipot
> >> http://www.edam.uhp-nancy.fr
> >> The light shines in the darkness, and the darkness has not
> >> overcome it.
> >> John
> >> 1:5.
> >> _______________________________________________________________________
> >>
> >
> > -----------------------------------------------------
> > Gianluca Interlandi, PhD gianluca_at_u.washington.edu
> > +1 (206) 685 4435
> > http://artemide.bioeng.washington.edu/
> >
> > Research Scientist at the Department of Bioengineering
> > at the University of Washington, Seattle WA U.S.A.
> > -----------------------------------------------------
>
>
>

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