FEP tutorial graph question

From: Christopher Hartshorn (cmhartshorn_at_wsu.edu)
Date: Wed Apr 29 2009 - 15:35:27 CDT

Hello all. I am having problems figuring out why my plot of dG vs.
lambda looks nothing like the plot in the FEP tutorial writeup. I
understand that I will not necessarily get the same ddG because of
various issues, but what I get is nothing like anything I have seen
(including all published sources). I have followed the tutorial to
the letter (minimize, equilibrate, and FEP with 100K iterations/lambda
step) with the tyr2ala part, but when I plot up the results they look
completely different (as in they curve up then down then up and then
down again not the smooth curve I see in most). I have a small jpeg
(73KB) of the graph I can send if need be. I generate these plots by
using the .fepout files lines that contain:

#Free energy change for lambda window [ 0 1e-05 ] is 0.0253223 ; net
change until now is 0.0253223
#NEW FEP WINDOW: LAMBDA SET TO 1e-05 LAMBDA2 0.0001

And then simply plotting the step versus the net change until now
(e.g. 1e-05 vs. 0.0253223 in the above example). Am I doing this
wrong? Plotting up the wrong data? I began doing this because I was
seeing the same results when I plotted up some FEP calculations that I
am doing on systems of mine and wanted to see if I could even get the
tutorial done correctly (which I clearly can not, meaning I must be
missing some point here because none of my graphs of dG vs lambda have
the smooth curves I have seen every where else).

Also, as a side note I have read of people who do an averaging of both
directions to get better results. But I am not sure if they mean
forward direction= (going from 0 to 1) and then 1 to 0 for reverse
direction or if they mean that forward=fading out (beta column=-1)
interaction of molecule of interest from 0 to 1 and reverse=fading in
(beta column=1) molecule of interest from 0 to 1 (although, I guess
those are probably the same things my question is with respect to NAMD
and which is the better way, if any, in practice). Is this averaging
actually better then going in the "more" correct direction to begin
with (e.g. the direction of lower entropy)?

Finally, and I will stop here, I thought I had read of people putting
restraints on (or even fixing) the molecule that is being faded in/out
for the FEP calculation. Is this normal practice?

Thank you very much in advance.

Chris Hartshorn

WSU

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