[gmx-users] free energy calculations blowing up

Fri Nov 11 22:39:59 CET 2005

Jonathan,

On 11/11/05, Moore, Jonathan (J) <JMoore2 at dow.com> wrote:
>
> David and David,
>
> Thanks for the suggestions. I'm not currently using soft cores for fear of
> the soft core bug in 3.2.1.
> http://www.gromacs.org/pipermail/gmx-users/2004-August/011830.html
>
> I haven't moved to 3.3 yet on any of my production machines because I'm
> holding out for 3.3.1, but maybe I'll have to give up waiting so I can use
> soft cores.

You _could_ just change that bit of the source code as described in that
post and recompile. I was using a CVS version of 3.2.1 from Nov. 2004 which
had that bugfix until very recently and the softcore stuff was working fine
for me.

It's worth noting, though, that there are number of other bugfixes
implemented in 3.3 which affect free energy calculations; it's not clear to
me whether the version I was using of 3.2.1, or the version you are using,
had all of these correctly implemented.

And just by way of advertisement, I'm currently using 3.3 and have been able
to compute free energies for turning off charges and vdW for a number of
small molecules in water. I've done so with the AMBER force field (from the
Pande group) and my results match what I was getting with the AMBER package.
This gives me a reasonable amount of confidence that things are working
properly. I've also computed the charging free energy of spc water in water,
the answer of which is known, and I get the correct answer.

I have, however, included this bugfix
http://www.gromacs.org/pipermail/gmx-users/2005-October/017495.html in my
3.3 installation. It's not clear to me that without the bugfix I necessarily
would have had problems, but...

David M., I guess this is the paper you were talking about, right?
> T. C. Beutler, A. E. Mark, R. C. van Schaik, P. R. Gerber and W. F. van
> Gunsteren. "Avoiding singularities and numerical instabilities in free
> energy calculations based on molecular simulations." Chem. Phys. Lett.,
> 222,
> 529-539 (1994).
>  http://dx.doi.org/10.1016/0009-2614(94)00397-1<http://dx.doi.org/10.1016/0009-2614%2894%2900397-1>

Yep, that's the one.

David

Thanks,
> Jonathan
> ____________________________
> Jonathan Moore, Ph.D.
> Research and Engineering Sciences - New Products
> Core R&D
> The Dow Chemical Company
> 1702 Building, Office 4E
> Midland, MI 48674 USA
> Phone: (989) 636-9765
> Fax: (989) 636-4019
> E Mail: jmoore2 at dow.com
>
> -----Original Message-----
> From: David Mobley [mailto: dmobley at gmail.com]
> Sent: Friday, November 11, 2005 3:27 PM
> To: Discussion list for GROMACS users
> Subject: Re: [gmx-users] free energy calculations blowing up
>
>
> Jonathan,
>
> To clarify slightly, the singularity for lambda->1 is when the lambda=1
> Hamiltonian corresponds to a completely disappeared particle. If you are
> changing on vdW radii into another vdW radii things are somewhat more
> complicated and it isn't clear to me that you really have the same sort of
> problem. I wouldn't be surprised if you did, though, but it would be at
> some
> intermediate lambda value. I would still try the soft core option,
> especially if your time series of dV/dlambda have anything that looks at
> all
> like shot noise.
>
> David
>
>
>
> On 11/11/05, David Mobley <dmobley at gmail.com> wrote:
> Jonathan,
>
> Two comments:
> (1) Although this wasn't your question, you might not want to run the
> simulations sequentially. I think previous work has shown that you can
> introduce some hysteresis this way, although the reference eludes me at
> the
> moment.
> (2) When changing vdW parameters, soft core helps a lot. From what you're
> describing it sounds like you are doing that. If you don't use soft core,
> dV/dlambda actually has a singularity for particle insertion as lambda->1
> (assuming the exponent of lambda is 1, which it is by default) and is also
> very susceptible to shot-type noise, and susceptible to crashes when
> forces
> get too large (which often happens near lambda=1). You can reduce the
> crashes somewhat by using smaller timesteps but this doesn't help with the
> shot noise or singularity problems. To understand why this happens you can
> look up van Gunsteren's paper from around 1992 introducing the soft core
> potential, or contact me directly for a brief explanation. If you have any
> trouble finding the reference I can look it up for you, but I don't have
> it
> in front of me right this instant.
>
> David Mobley
> UCSF
>
>
>
>
>
> On 11/11/05, Moore, Jonathan (J) <JMoore2 at dow.com > wrote:
>
> I have a question about free energy calculations.
>
> I'm performing several different simulations where the hydrogen of certain
>
> hydroxyls on my molecule is replaced with a methyl group. It's a united
> atom model, so the change from hydrogen to methyl doesn't change the
> number
> of sites. I have a single molecule of interest in SPC water (see more
> details below). I'm experiencing the problem that on occasion the system
> blows up. I've had no problems like this previously when simulating only
> one state or the other (methylated or unmethylated), so I think the
> problem
> is due to the free energy calculation. Unless I've made an error in
> setting
> up the free energy calculation, I assume my problem is that the system
> isn't
> stable for the timestep that I'm using (2 fs) and how fast I'm changing
> lambda (I'm incrementing lambda by 0.05 followed by 200 ps of simulation
> before increasing it again).
>
> Is it common to either decrease the time step or use lambda increments
> smaller than 0.05 when doing free energy calculations this way? I'm
> planning to try both to see if they fix the problem, but I'm curious if
> anyone else has had a problem like this. I'm not using soft cores, but
> maybe I have to?
>
> Also, I'm specifying the atom types like this ( i.e., with the mass being
> taken from the .atp file):
>
> [ atoms ]
> ; nr type resnr residu atom cgnr charge
> 6 H 1 H000 HO3 2 0.410
>
> Therefore, when I specify the B state, I do it like this (i.e. with out
> specifying the change in mass, assuming the GROMACS will also get the B
> state mass properly from the .atp file):
>
> [ atoms ]
> ; nr type resnr residu atom cgnr charge
> 6 H 1 H000 HO3 2 0.410 CH3 0.180
>
> Should that work OK? It wasn't obvious to me where to look in the output
> to
> make sure it is. I assume I'll be able to answer that question myself when
> 3.3.1 is released and I can use "gmxcheck -ab"
>
> More details:
> v. 3.2.1, single precision
> 2 fs timestep
> All bond lengths constrained (LINCS)
> Nosé-Hoover thermostat with the polymer and solvent coupled separately;
> 0.4
> ps time constant
> Berendsen barostat with 0.5 ps time constant and 4.5x10-5 bar -1
> compressibility
> Triple-range cut-off method
>
> Thanks,
> Jonathan
>
> ____________________________
> Jonathan Moore, Ph.D .
> Research and Engineering Sciences - New Products
> Core R&D
> The Dow Chemical Company
> 1702 Building, Office 4E
> Midland, MI 48674 USA
> Phone: (989) 636-9765
> Fax: (989) 636-4019
> E Mail: jmoore2 at dow.com
>
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