[gmx-users] FEP trajectory errors

Mon Jan 21 17:19:19 CET 2008

The distortion was occuring because my position restraint potential
was too weak. Increasing the force constant keeps the base in the
right conformation.

I believe my topology is correct, but it seems that turning off the
VdW parameters causes the base to distort. I will look into this more.

Also, even with sc_alpha=0.5, I'm still experiencing this weird
"freezing" when lambda=1.0. The trajectory proceeds normally for about
2.1 ns, then all of a sudden all motion freezes and the atoms simply
vibrate about their "equilibrium positions". Any other ideas what
might cause this?
Thanks,
Bob

On Jan 21, 2008 3:39 AM, Maik Goette <mgoette at mpi-bpc.mpg.de> wrote:
> Robert
>
> A value for alpha of 0.5 should work, although I tested some different
> alphas with different test systems and I have to say, that a proper
> value can be between 0.2 and 0.7 depending on the system itself.
> The distortion, you describe is really strange. I calculated DNA and
> single bases a lot and never saw something like that. Even a fully
> "dummy-base" is stable, if your topology is correct. The bonded terms
> are sufficient to keep it in the right conformation.
> Are you sure, your position restrains in the topology are used with the
> correct structure file?
>
> Maybe, I should also mention, that, especially with such large
> perturbations as a full DNA-base, you should split your topology into 2,
> where you switch off the QQ hardcore and the VdW softcore in two steps.
>
> Regards
>
> Maik Goette, Dipl. Biol.
> Max Planck Institute for Biophysical Chemistry
> Theoretical & computational biophysics department
> Am Fassberg 11
> 37077 Goettingen
> Germany
> Tel.  : ++49 551 201 2310
> Fax   : ++49 551 201 2302
> Email : mgoette[at]mpi-bpc.mpg.de
>          mgoette2[at]gwdg.de
> WWW   : http://www.mpibpc.gwdg.de/groups/grubmueller/
>
>
> Robert Johnson wrote:
>
> > Thank you David and Maik for your detailed replies. Yes, I am trying
> > to obtain an absolute free energy of binding. My thermodynamic cycle
> > is:
> >
> > NT+DNA(adsorbed) -> NT+ DNA(desorbed)  (obviously this is not the one
> > that I'm obtaining with the alchemic method)
> >
> > Thus, the one I'm using in the simulation is:
> >
> > Water + NT + DNA(adsorbed) -> Water + NT + nothing (DNA dissapears)
> > Water + DNA -> Water + nothing
> >
> > Any suggestions about this? I will check out your recent publications.
> >
> > I believe my topology is properly formatted. I wasn't expecting the
> > large distortions because I was using position restraints. Thus, I was
> > expecting the base to remain in about the same geometry. Perhaps I
> > will increase the force constant for the restraining potential.
> >
> > I am going to repeat some of these computations using sc_alpha=0.5.
> >
> > Thanks for your help.
> > Bob
> >
> > On Jan 17, 2008 2:24 PM, David Mobley <dmobley at gmail.com> wrote:
> >> Robert,
> >>
> >>> I'm computing the free energy of binding of a DNA base on a carbon
> >>> nanotube. I think it's a pretty simple calculation and I'm proceeding
> >>> in a very standard way. This is what I'm doing:
> >> An absolute free energy? This isn't necessarily straightforward --
> >> there are a lot of wrinkles. Some of my recent work has some
> >> discussions if this if it's helpful.
> >>
> >>> I have the optimal orientation of the base on the nanotube. I'm
> >>> constraining the positions of the base atoms with a soft harmonic
> >>> potential.
> >> OK, that's a good idea for standard state reasons (see the 2003
> >> Boresch paper) among other things.
> >>
> >>> I then am running two different FEP calculations: one where I turn off
> >>> the charges on the base atoms and a second where I then turn off all
> >>> the lennard-jones parameters for the base atoms. For each of these I
> >>> use the following:
> >>> delta_lambda = 0
> >>> sc_alpha = 0.7
> >>> sc_power = 1
> >>> sc_sigma = 0.3
> >>>
> >>> I run a series of trajectories at constant lambda values from 0 to 1.
> >> OK. I have some information posted on what I think the best settings
> >> are for these on alchemistry.org, especially at
> >> http://www.alchemistry.org/wiki/index.php/Best_Practices. It is still
> >> in progress but may be somewhat helpful. I doubt this is the source of
> >> your problems though, although I prefer a sc_alpha = 0.5 which may
> >> improve the situation somewhat.
> >>
> >>> However, I notice some problems with the trajectories when I turn off
> >>> the LJ parameters. As lambda is varied from 0 to 1, it seems that the
> >>> position restraints no longer are being applied. Additionally, the DNA
> >>> base geometry starts to become severely distorted at lambda values
> >>> greater than about 0.6. This happens despite the fact that I am not
> >>> perturbing the internal bonded interactions of the base. Here is a
> >>> sample of my topology (included just the first line of each section):
> >> Hm, on the position restraints, depending on your version of gromacs
> >> you may need to additionally specifiy the B state position restraints,
> >> else these may be assumed to be zero. I believe you can do this by
> >> adding additional columns in your posre.itp that give the B state
> >> parameters.
> >>
> >> In terms of distortion, it's not clear to me why you think the
> >> molecule should *not* be distorted once you turn off the LJ
> >> interactions (which includes internal LJ interactions). The bonded
> >> parameters (especially torsions) are of course derived after LJ
> >> parameters are already fitted, in most cases, so they only can be
> >> relied on to give meaningful conformations when the LJ interactions
> >> are on. The beauty of the thermodynamic cycle approach, though, is
> >> that you can (at least in principle) get correct binding free energies
> >> even if your molecule of interest samples wacky, artificial
> >> conformations when it's noninteracting.
> >>
> >>> Also, I am experiencing additional problems when lambda=1. After about
> >>> 2ns, all the motion in the system begins to freeze and all the atoms
> >>> simply vibrate about a fixed position. Soon after that the simulation
> >>> crashes.
> >> My experience has been that sc-alpha = 0.7 can lead to a fairly steep
> >> dV/dlambda and some large forces near lambda=1, which is why I
> >> recommend sc-alpha = 0.5. This parameter is actually fairly sensitive.
> >> This *could* lead to crashes, but I don't know about
> >> freezing/vibrating.
> >>
> >> Let me know if this helps.
> >>
> >> Best wishes,
> >> David Mobley
> >> UCSF
> >> http://www.dillgroup.ucsf.edu/~dmobley
> >>
> >>> Can anyone comment on what's going on here?
> >>> Thanks,
> >>> Bob Johnson
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