Re: FEP tutorial graph question

From: Chris Harrison (char_at_ks.uiuc.edu)
Date: Thu Apr 30 2009 - 10:23:25 CDT

Chris,

Ok, if using NAMD2.7b1 you should make sure you're using the following
parameters (at least unless you later decide to better benchmark these
parameter values for your own system):

fepElecLambdaStart 0.5
fepVdwLambdaEnd 1.0
decouple on

Now, I'll try to answer your questions, with some overlap to Jerome's
answers. Please make sure to read his email as he provides the background
and references that you should absolutely read.

QUESTION 1:
On Wed, Apr 29, 2009 at 3:35 PM, Christopher Hartshorn
<cmhartshorn_at_wsu.edu>wrote:
..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 generate these plots by using the .fepout files lines ...
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?

SUGGESTION 1:
That depends. Are you removing the lines in *.fepout that correspond to the
fepEquil steps? If not, and without seeing your plot, I wonder if your
curving up and curving down might be due to the verbatim plotting of the
lines of this file and not deleting the lines corresponding to equilibration
of each bin. Also, plotting the lines verbatim from *.fepout is really
only the very beginning, but for a quick and dirty evaluation of the energy
change you can look at the last line of each bin which outputs the overall
free energy change for that bin. Further, you should insure that each bin
is converged. I cannot emphasize that enough. If your bin is not converged
then you are undersampling and therefore have a likely "incomplete" free
energy evaluation of that bin. Finally, you should of course perform a
suitable integration/analysis like a Gram-Charlier analysis. See the below
refs as a jumping-off point:

1. Dixit and Chipot, JPCA 105(42):9795 (2001)
2. Free Energy Calculations, Chipot (
http://www.amazon.com/gp/product/3540384472) Start specifically with
section 2.9.3 (around pg 64)
With SpringLink Access, try:
http://www.springerlink.com/content/x611656584473g84/

It should be noted however, that when using the softcore approach (which is
now default in NAMD) that the "FEP path" doesn't always "look" like it makes
sense unless you realize at what values of lambda what specific types of
atomic interactions are being perturbed. In the FEP of NAMD2.6 all atomic
interactions were uniformly perturbed. Now, in NAMD2.7b1 with softcore,
different types of interactions (ie vdW vs. electrostatic) are decoupled
with different scaling values according to a given lambda value.

QUESTION 2:
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)?

SUGGESTION/ANSWER 2:
This is has been commonly called "doublewide sampling." Please refer to
Jerome's earlier post and Kofke references therein for more in depth
explanation and a suggestion of how to bootstrap this at present. We have
experimental code that does this within NAMD, but it is not quite ready for
primetime. Should be ready soon.

QUESTION 3:
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?

SUGGESTION/ANSWER 3:
Yes, as Jerome indicated, this is often used in "doubly decoupled" FEPs.
Please persue the references Jerome listed for more info. We'll be looking
at how this optional capability might be added to NAMD later in summer.

C.

--
Chris Harrison, Ph.D.
Theoretical and Computational Biophysics Group
NIH Resource for Macromolecular Modeling and Bioinformatics
Beckman Institute for Advanced Science and Technology
University of Illinois, 405 N. Mathews Ave., Urbana, IL 61801
char_at_ks.uiuc.edu                            Voice: 217-244-1733
http://www.ks.uiuc.edu/~char               Fax: 217-244-6078
On Wed, Apr 29, 2009 at 7:52 PM, Christopher Hartshorn
<cmhartshorn_at_wsu.edu>wrote:
> Chris,Yes, sorry I forgot to add that and I had told myself to do so
> before hand.  I am using the latest 2.7b1 executable mainly because I was
> under the impression that for what I wished to do (double-annhilation of a
> very small antimicrobial peptide), that it would be my best option (before
> the beta was released as an executable I had been using a CVS version from
> last December).
>
> Thank you
>
> CMH
>
> On Apr 29, 2009, at 2:17 PM, Chris Harrison wrote:
>
> Chris,
>
> Before I answer your many questions, which version of NAMD are you using?
> If the cvs version, on what date was it checked out or downloaded?  There
> are significant differences between the FEP implementations depending upon
> the NAMD version.
>
>
> C.
>
>
> --
> Chris Harrison, Ph.D.
> Theoretical and Computational Biophysics Group
> NIH Resource for Macromolecular Modeling and Bioinformatics
> Beckman Institute for Advanced Science and Technology
> University of Illinois, 405 N. Mathews Ave., Urbana, IL 61801
>
> char_at_ks.uiuc.edu                            Voice: 217-244-1733
> http://www.ks.uiuc.edu/~char <http://www.ks.uiuc.edu/%7Echar>
>   Fax: 217-244-6078
>
>
>
> On Wed, Apr 29, 2009 at 3:35 PM, Christopher Hartshorn <
> cmhartshorn_at_wsu.edu> wrote:
>
>> 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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