Re: [AMBER] accuracy of FEW free energy calculation

From: Jason Swails <>
Date: Sun, 21 Jun 2015 13:00:55 -0400

On Sun, Jun 21, 2015 at 3:10 AM, Albert <> wrote:

> If you are working for Schrodinger, then you can skip all my comments in
> the mail list since you will find countless explanations, or excuses,
> for the unexpected results.
> (1) I wish I could repeat the JACS paper result by myself which is not
> feasible for my. (a) FEP+ must run in the same machine and it requires
> at least 4 powerful Tesla GPU workstation to do this. I only have 1 such
> kind of machine which gives me 0.5 compounds/day. In the JACS benchmark,
> it refers to hundred of compounds which means it will take 1 year to be
> done

​Then run shorter simulations and see if their results make sense given
what you *can* reproduce. Or just try and reproduce some of their data
points, not all of them. These are all useful strategies for figuring out
if you're using their software "correctly".

> (b) checking the quality of the publication, it is the duty of the
> JACS editor instead of mine.

​I have now read the paper, and it seems to me to be of satisfactory
quality, and their results seem to fall within expected ranges of
performance based on my experience. Verifying reproducibility for every
published study is well beyond the scope of editor (*and* reviewer)
responsibilities for obvious reasons.

(2) Of course Schrodinger is not stupid, because they are too SMART to
> do many things including cheating. I know Schrodinger treat many
> scientist as their cheap labors and them they labeled themselves as
> scientist.

​Look at the Schrodinger executives:
Of the 16 people there, 10 are Ph.D. scientists. Even 1 out of their 3
business development leaders is a Ph.D. chemist. OpenEye operates the same
way. They are a company developing scientific software *led by
scientists*. Recognized and respected scientists in the field, I may add.

Unfortunately, this won't change the businessman's
> personality. Making money is the only goal they care and to achieve it,
> anything possible could happen. So, many original free open source
> software is no longer free after in-cooperated into Schrodinger.
> However, this doesn't necessarily mean it becomes better after
> commercialization. One typical example is Modeller in DiscoveryStudio:
> the efficiency become much slower than the open source version and even
> sometimes we find some problems of accuracy.

​Of course. Open source and commercial software have different funding
models. Both work and have advantages over the other (look at NAMD -- it's
released free of charge but has received steady and substantial development
funding for over a decade).​

> (3) Unfortunately, my colleague and I working on Schrodinger so many
> years and we never have such good luck that Glide scoring function never
> works fine in ranking compounds affinity.

​Have you tried alternatives? Do any of them work better? If so, I
suggest switching (for obvious reasons). There are reasons not everyone in
the field uses GLIDE for docking.

> (4) In the JACS paper and recent FEP+ online Webex, Schrodinger showed
> many different targets and all of them looks perfect. It is a kind of
> promise to the users that this tool can guarantee a good results for
> nowadays many popular system. I am lucky, the target working on belongs
> to the one of the perfect class they showed in the benmark. But I am not
> lucky enough, since FEP+ from Schrodinger doesn't work at all for me.
> Of course you can claim in that way. For the same target, you tell
> people sometimes it works and some times it doesn't. This only ruin this
> tool to be not working at all, since before new compounds synthesizing
> out, this tool is not competent to predict whether it is going to work
> or not.

​Unfortunately that describes every computational method in existence.
Obviously not ideal, but the field seems to be advancing regardless.

For my case, there are 5 class of compounds for the same target and,
> unfortunately, none of them works by Schrodinger FEP+. However, I
> obtained very impressive results from inexpensive methods MM/PBSA which
> gives me R^2=0.5-0.8.
> ​

​Then use that instead. Obviously that serves me best as I've written a
large part of the code and am a coauthor on the corresponding

Good luck,

Jason M. Swails
Rutgers University
Postdoctoral Researcher
AMBER mailing list
Received on Sun Jun 21 2015 - 10:30:02 PDT
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