[gmx-users] FEP trajectory errors

[Maik Goette]

Do really all atoms "freeze". So also the atoms, which are not perturbed?
Can you post your mdp-file?

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:
> 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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