Re: [AMBER] accuracy of FEW free energy calculation

From: filip fratev <>
Date: Fri, 19 Jun 2015 22:25:54 +0000 (UTC)

Hi Ross and Albert!

Albert you are definitely lucky to have access to the FEP+ module ;)  Now they use the OPLS3 FF instead OPLS-2.1, which seems to be much better for proteins. Try it. I heard that good results have been obtained for PPARy and many other targets, probably your system is not trivial?   

Ross, in principle what steps, if it is possible at all, could be performed to mimic Schroedinger's protocol?
For instance, I suppose that one can make his own parametrization of the ligands, instead GAFF, to achieve better FF for them. Then is it possible the REMD protocol that they use to be implemented? Finally if you find money to port that pmemd module to GPU would be great!

I have an off topic question. I observed that using the MC barostat can't find the correct ligand binding mode in a target protein but using "regular" simulation I can. I repeated the simulations a couple of times. Probably this is by some accident but I was wondering whether the use of this barostat might have such great impact?


     On Saturday, June 20, 2015 12:31 AM, Ross Walker <> wrote:

 Hi Albert,

FEW / TI calculations are notoriously difficult to converge. I suspect a large number of issues are due to lack of convergence. If I had a dollar for every time I saw people give talks where they knew apriori what the experimental value was and they ran their simulations until they got the experimental value they were expecting I would have no problem funding my research group.

I can't say for sure since I don't have any evidence but my guess (gut feeling?) would be in terms of the 2015 paper either:

1) Your results are not converged hence the poor agreement.

2) The results in the paper are not converged.

3) Molecules / Systems that did not agree well with experiment were excluded from the results in the paper in some way.

In reality I suspect a combination of all 3.

All the best

> On Jun 19, 2015, at 1:44 PM, Albert <> wrote:
> Dear:
> I've got some concern on the accuracy of FEW tool for free energy
> calculation.
> According to the original FEW paper which published on Journal of Comp.
> Chem 2013 (34) 965-973
> in Table  2, the correlation factor for this TI calculation results
> seems to be poor, it is only R^2=0.25, R^2=0.26 for method 1 and method
> 2 respectively. I am not convinced that this is a confident methods for
> widely use in drug discovery.
> More recently, Schrodinger released their FEP Mapper tool which make
> ligand free energy circle to improve the accuracy. They published this
> technology in J. Am. Chem. Soc., 2015, 137(7), 2695–2703 recently. In
> that paper, the showed "perfect" correlation plot between prediction and
> experimental data. However, recently I used this "perfect" tool coupled
> with so called OPLS-2.1 FF to predict my system. After 1 months running
> on a powerful GPU workstation for 12 testing candidates, I only got
> R^2=0.16 !!! Interestingly, with exactly the same system and starting
> structure, I run MM/PBSA which was done in 3 days and it gave me
> R^2=0.79 !!!
> Now I am really curious about nowadays so called popular methods and
> their accuracy.
> Does anybody did any benchmark of FEW in Amber?
> I would be very interested in to see the results.
> regards
> Albert
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Received on Fri Jun 19 2015 - 15:30:02 PDT
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