Re: Selection of alchElecLambdaStart

From: Jérôme Hénin (jhenin_at_ifr88.cnrs-mrs.fr)
Date: Tue Sep 28 2010 - 14:51:36 CDT

Hi Courtney,

You raise an interesting question, however there is no general
agreement on the answer. You may be interested in discussions of "good
practices":
http://pubs.acs.org/doi/abs/10.1021/jp102971x
and "best practices" (gosh, those guys keep raising the stakes):
http://www.alchemistry.org/wiki/index.php/Best_Practices

Consider Guideline 3 in the second document, which amounts to saying
that alchElecLamdbaStart should be equal to alchVdwLambdaEnd. The idea
is not backed by formal proof or published numerical data, and you'll
note that the authors of that page were careful to call it a
guideline. Yet, another argument in favor of this is that it makes the
alchemical process conceptually simpler by identifying separate
stages.

This choice is also coupled with complex decisions on how many
lambda-point to use and how much to sample each of them. The errors
you run into seem to be linked to an insufficient number of
lambda-points.

As you can see, there are so many parameters at play that so far it
has been impossible to define an optimal recipe. Fortunately, for each
problem, there is a range of reasonable choices leading to simulations
that behave quite well.

Best,
Jerome

On 28 September 2010 17:50, Courtney Taylor <courtney.b.taylor_at_gmail.com> wrote:
> I have a question regarding the appropriate selection of
> alchElecLambdaStart. I am working on simulations of a protein in water and
> over a surface to calculate relative binding free energy using the
> alchemical TI method (not FEP). I gradually mutate a residue from wild-type
> (say, tyrosine) to mutant (alanine). I completed the tutorial that looked at
> this same mutation with solvation free energy and was able to reproduce the
> results.
>
> I've run various test simulations, but run into issues when I test varying
> the electrostatic lambda start. With decouple off, varying this is not an
> issue. With decouple ON, however, if I lower this to 0.1 I get extremely
> high ∆∆G values (300-400 kcal/mol, when I expect ~10 or less). I also get
> error messages from namd2_ti.pl stating that the integral for the window is
> too high.
>
> So my question is: What is the logical way to select alchElecLamdbaStart? Is
> there a specific reason why the default is 0.5? Is there a calculation I can
> perform to optimize this selection--i.e. in the user guide it states "As
> lambda increases, once the particles are repelled it becomes safe to turn on
> TI electrostatics" so is there a way to estimate when these particles are
> repelled?
>
> Correspondingly is there a logical way to set alchVdwLambdaEnd other than
> the default of 1.0?
>
> Thanks. I want to make sure I have all of the variables correct to get an
> accurate result.
>
> Courtney Taylor
> PhD Candidate
> Department of Chemical and Biomolecular Engineering
> Vanderbilt University
> (225)-771-8554
> (615)-343-3257
>
>

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