Re: AMBER: large RMS fluctuations in turning off VDW interactions by TI

From: Holly Freedman <>
Date: Wed, 4 Jul 2007 13:53:01 -0600

Hi Thomas,

Thanks for your answer. Actually my fluctuations are worse than you mentioned. Here is what I have
for fluctuations:

At lambda = 0.01592, 4.7916
At clambda = 0.08198, 4.9031
At clambda = 0.19331, 5.6905
At clambda = 0.33787, 7.5437
At clambda = 0.5, 11.4195
At clambda = 0.66213, 24.0413
At clambda = 0.80669, 48.7498
At clambda = 0.91802, 133.4857
At clambda = 0.98408, the program won't run - I think because velocities get too large

So I will have to throw out the values from clambda = 0.91802 on.
I had previously thought that the RMS fluctuations give the error, but it sounds like this isn't right
from what you wrote below. I'm not sure how you are estimating errors from the RMS fluctuations.

I am really only intersted in the free energy change associated with turning off the WCA attractive
potential, and so maybe I can do OK with just extrapolating the numbers I have for clambda less than
or equal to 0.80669 down to zero at clambda = 1, considering that up until clambda = 0.80669 the
repulsive forces are all still likely on.

Best regards,

> Hi,
> sorry, I am only transiently accesing the net right now and it looks like
> I deleted half of this discussion before I realised that its on my topic.
> I think David and Dave have pointed out the important points already,
> menaing that the fluctuations you see in turning of a vdw-particle
> (disappearing an atom) are absolutely to be expected. Without klambda>1
> you have no hope of ever getting a free energy curve that is suitable for
> numerical integration.
> The recent paper to which David pointed you indeed discusses precisely
> that and compares several different scaling schemes, as does the van
> Gunsteren paper mentioned earlier. From my experience on the solvation
> free energies, using separation shifted 'softcore' potentials looks like
> the best option you can have in terms of curve shape that is good for
> integration and dvdl-histograms that make it likely to get a sound average
> without doing huge amount of sampling. However, at least for the simple
> small molecule solvation free energies I looked at, the klambda=6 option
> is not much worse and should easily give you good results if you dont have
> access to softcore potentials. I am not sure if this is still the case if
> a more complex conformational space like a ligand-protein complex is
> studied (as David also pointed out already). We will do more on a test
> system there in the near future, but for now I would expect that you have
> a good chance at least trying to study your transformation with just the
> klambda option.
> If I remember right (and correct me if I dont) you mentioned dvdl-rms of
> ca 30kcal/mol. While this is more than I saw in a disappearing toluene, it
> is by no means prohibitively large. If you get dvdl-correlation times of
> say 100fs on a 1 ns run, then this would correspond to a standard error in
> the range of < 1kcal/mol and that only for the worst part of your free
> energy curve. So chances are good that you will get a decent free energy
> with a reasonable standard error.
> Kind Regards,
> Thomas
> >> minor. Thomas is travelling right now, but maybe when he reads this, he
> >> can
> >> post the RMS fluctuations from this studies.
> Sorry, I dont have my data here, so I'll have to refer you to the preprint
> of our publication available on David Mobley's homepage.
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Department of Physics, University of Alberta
Edmonton CANADA
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Received on Sun Jul 08 2007 - 06:07:15 PDT
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