[gmx-users] FEP trajectory errors

[Robert Johnson]

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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