Re: Alchemical transformations and DDG of point mutations

From: Chris Chipot (
Date: Thu Dec 13 2012 - 12:47:46 CST

> 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
The light shines in the darkness, and the darkness has not overcome it.
                                                               John 1:5.

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