[gmx-users] free energy: annihilation

[David van der Spoel]

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.
<cynical>
Or: for interesting molecules you're out of luck, unless you're lucky
</cynical>



-- 
David.
________________________________________________________________________
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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