[gmx-users] free energy: annihilation

David van der Spoel spoel at xray.bmc.uu.se
Tue Aug 29 19:34:49 CEST 2006

David Mobley wrote:
> David,
>> > Yuguang reminds me of something else... I just did a bunch of
>> > hydration free energy calculations for a large set of small molecules.
>> > These tend to be pretty accurate for stuff that is mostly nonpolar,
>> > but the larger the charges are, the bigger the deviation from
>> > experiment can be. In particular, I tested a bunch of different charge
>> > models; the average error is correlated with the dipole moment, among
>> > other things. Generally, I would say that the larger your hydration
>> > free energies are, the worse you will probably do compared to
>> > experiment, unless you have some way of getting really terrific
>> > partial charges or something. If DMSO has high partial charges, it
>> > seems quite possible that the "right" answer for the hydration free
>> > energy with those partial charges may end up being quite different
>> > from experiment.
>> >
>> This seems weird, the only physical reason I can think of would be a
>> contribution due to depolarization (as in Berendsen's SPC/E model). For
>> water this would be roughly 4 kJ/mol. However for DMSO in my case it
>> would be less, since it has a high dipole in the gas phase as well.
>> Obviously if the model is poor results will be poor.
> No, not systematic. Just think of it this way: If you have only small
> partial charges, the only thing that can possibly  be wrong that will
> make much difference is the LJ parameters or the water model. If the
> partial charges are larger, they can also make a big difference in the
> hydration free energy. Thus, for mostly apolar molecules, you can't do
> *too* badly, since water molecules and LJ parameters are generally
> decent. But for polar molecules, if your partial charges are really
> bad, you can do very badly.
> In other words, all I'm saying is basically that the larger the
> hydration free energy is, the more wrong it can, which is fairly
> obvious. :)

It still seems strange, if one can get a lot of other properties 
correct, like DHvap, dielectric constant, density, diffusion constant etc.
Unfortunately my simulations are converging very slowly, but I hope to 
have more conclusive results soon.

> I actually found that, for my test set, depending on the partial
> charges I used, I could get hydration free energies for polar
> molecules that varied by more than a factor of 2. And these were all
> "sensible" charge sets in some sense (QM-based, fit using RESP).

Reasonable Estimate of Simple Point charges...

It's not that I know of any better method to do it, but the QM levels of 
theory typically used for computing charges are *very* low, and far from 
convergence to the basis-set limit. In addition RESP is not a good 
method, because the problem is underdetermined... You know, Peter 
Kollman once told me that they did quantum calculations followed by RESP 
and then multiplied the charges by 0.9.

> The moral of the story is that basically you should be careful what
> charges you use, and be aware that it is possible for the charge set
> to mess things up a whole lot.
Or: for interesting molecules you're out of luck, unless you're lucky

David van der Spoel, PhD, Assoc. Prof., Molecular Biophysics group,
Dept. of Cell and Molecular Biology, Uppsala University.
Husargatan 3, Box 596,  	75124 Uppsala, Sweden
phone:	46 18 471 4205		fax: 46 18 511 755
spoel at xray.bmc.uu.se	spoel at gromacs.org   http://folding.bmc.uu.se

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