Re: [AMBER] accuracy of FEW free energy calculation

From: Ross Walker <>
Date: Fri, 19 Jun 2015 14:31:32 -0700

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 - 15:00:02 PDT
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