[gmx-users] free energy: annihilation

[David Mobley]

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.

David


On 8/26/06, Mu Yuguang (Dr) <YGMu at ntu.edu.sg> wrote:
> Hi David,
> Recently I repeated some free energy solvation calculations according to
> the tutorial by David Mobly. I agree with him that when you do DMSO
> which has some high partial charges, You should do calculations with
> Coulomb and VdW separately. Otherwise unphysical results appear.
>
> Best regards
> Yuguang
>
> Dr. Yuguang Mu
> Assistant Professor
> School of Biological Sciences
> Nanyang Technological University
> 60 Nanyang Drive  Singapore 637551 Tel: +65-63162885 Fax: +65-67913856
> http://genome.sbs.ntu.edu.sg/Staff/YGMu/index.php
>
>
> -----Original Message-----
> From: gmx-users-bounces at gromacs.org
> [mailto:gmx-users-bounces at gromacs.org] On Behalf Of David Mobley
> Sent: Saturday, August 26, 2006 9:05 PM
> To: Discussion list for GROMACS users
> Subject: Re: [gmx-users] free energy: annihilation
>
> David,
>
> > I'm trying to annihilate a complete DMSO box at constant volume. The
> > dG/dlam values converge nicely but when I integrate the curve I get a
> > Helmholtz energy that is almost exactly a factor of two different from
> > the experimental value.
>
> Maybe this is too basic, but are you doing the transformation in
> vacuum also and subtracting? I assume you are trying to compute
> something like a hydration free energy, which means you have to
> complete a thermodynamic cycle that takes you from the full molecule
> in water to the full molecule in vacuum. I don't know any way to do
> this  in GROMACS currently without also doing a separate vacuum
> calculation, because of the intramolecular interactions.
>
> > Am I forgetting something here? Should I treat the intramolecular
> > degrees of freedom in a special manner?
>
> You can, but you don't have to. One thing that can sometimes help
> convergence is to only turn off the intermolecular LJ interactions,
> which you can do by modifying the pairs list and explicitly stating
> appropriate LJ parameters, or (presumably) by using the new pairs
> types that Berk implemented, although I still haven't tested these
> myself.
>
> >Currently I am only turning off
> > the LJ and Coulomb terms. Should I turn off the angles and dihedrals
> as
> > well?
>
> No, you don't want to do that.
>
> The other thing that can make some difference is your protocol. In
> particular:
> (1) Are you turning off the LJ and Coulomb terms simultaneously? I've
> always found that it is a lot harder to converge this calculation and
> get reliable answers than if you do the Coulomb interactions first and
> then do the LJ interactions.
> (2) What soft core parameters are you using for the LJ interactions?
> Some work much better than others.  (My free energy tutorial has some
> information about doing the LJ transformation. If you want to do
> something really basic, you could try reproducing my value for
> methane:
> http://www.dillgroup.ucsf.edu/group/wiki/index.php/Free_Energy:_Tutorial
> .
> I also list the soft core parameters that are "optimal" there.)
> (3) Make sure your PME parameters are good enough; sometimes free
> energy calculations can be pretty sensitive to this sort of thing
> (4) How curved is your dV/dlambda plot? TI can end up making a
> nontrivial amount of integration error, especially if you have nearly
> equal positive and negative areas under the curve (in which case the
> integration error could be on the same order of magnitude as the total
> integral).
>
> David
>
>
> > 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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