Selection of alchElecLambdaStart

From: Courtney Taylor (courtney.b.taylor_at_gmail.com)
Date: Tue Sep 28 2010 - 10:50:24 CDT

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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