[gmx-users] Re: 1-4 interactions free energy calculations

Justin Lemkul jalemkul at vt.edu
Wed Jun 26 04:53:29 CEST 2013

On 6/25/13 4:36 PM, Sonia Aguilera wrote:
> Hi Justin,
> Thank you for your answer. I’m performing several tests to see what is the
> best for my system. The reason I decided not to couple the intramolecular
> interactions is because I think that the annihilation of the molecule will
> lead to very extreme configurations and that will affect my phase-space
> overlap. I know I can just increase the number of intermediate states, but I
> wanted to first test my theory. Also, I have limited resources to run.
> There is a gap between the indirect and direct calculation methods  for my
> system. If I set up couple-intramol=no, then I can´t use domain
> decomposition but particle decomposition in all simulations (charge groups
> are too big, and there is no domain decomposition… ) and I got the 1-4
> interactions warning. If I restrain the h-bonds, then the minimization
> converges but not to Fmax less than 100 in only 499 steps and 12 minutes (8
> cores machines). If I continue and run the NVT stabilization, then it takes
> 17h20min to complete only 100 ps, and I still got the 1-4 interactions
> warning. I still have to run the NPT and 3 ns MD, which will take too much
> time. I think it worth it  because I think it will help with the phase-space
> overlap, and I will only have to perform 20 series of simulations (vdw and
> coulomb separately) to get the free energy change.
> On the other hand, if I set up couple-intramol=yes, then I have to run 20
> extra simulations in vacuo to counter the annihilation effect. I think that
> it will also affect the phase-space overlap. The good thing is that I can
> use domain decomposition and the minimization converges to machine precision
> (takes 7000 steps and around 40 minutes in a machine with the same
> characteristics that the previous one). Also, the same 100-ps NVT takes only
> 3h20min. If I think of the overall picture, it seems that the total time I
> will spend doing dd (coupleintramol=yes) rather than pd (coupleintramol=no)
> will be less. However I’m worried about the phase-space overlap and the
> available resources I have for running since it makes difficult to just
> increase the intermediate states.

You may be able to tweak the DD setup using mdrun command line options.  You 
haven't posted specific messages, which would have been useful.  It sounds like 
you may have a problem with your charge groups, and if that's coming from grompp 
then you have a topology problem.  If it's coming from mdrun, then again it's 
probably just a matter of tweaking some things.  Normally, one does not have to 
adjust the DD setup, but if you have long-range interactions that are being used 
by the free energy code, that may be necessary.

> Also, I think I can try doing the same but with the 4.6.1 version. It looks
> like I can now couple both vdw and coulomb in the same simulation
> (http://www.alchemistry.org/wiki/GROMACS_4.6_example:_Direct_ethanol_solvation_free_energy).
> I have also wanted to try expanded ensemble to improve my sampling, but I
> have not found that much documentation about the implementation on gromacs.
> It would be great if you can provide an example.

Michael provided some good commentary here; there's nothing I can add.

> So, do you know another way to improve my sampling and the phase-space
> overlap that can help me to solve my problem?  Also, I’m working with a
> charged molecule. Would it help in any aspect if I neutralize the system?

PME should compensate for the net charge, IIRC.



Justin A. Lemkul, Ph.D.
Research Scientist
Department of Biochemistry
Virginia Tech
Blacksburg, VA
jalemkul[at]vt.edu | (540) 231-9080


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