[gmx-users] FEP

[paloureiro at biof.ufrj.br]

Hi David,

I am not an expert in FEP, but I have used that method to try to answer the
following question: if there was a free energy difference between a 
system with
a Na+ ion inserted by the best-potential method or randomly.
I performed a series of MD runs (several lambdas) with annihilation of the ion
(with reaction field electrostatics) and, then, another series with 
slow-growth
of the ion, starting with the last frame of the previous series of simulations
(Please, see the attached file - fep.jpg)
The problem was motivated by the fact that a Na+ ion was "inserted" in 
a rather
dehydrated environment - and I questioned the physical/biological relevance of
that.
Maybe the errors associated with the rection field method are cancelled 
as long
as one is using a delta(deltaG/deltaLambda).
But I agree with you that a PMF will be a better choice for the particular
system under discussion.

Regards.

Pedro.


>
> I am rather nervous about doing FEP/TI for disappearing charged molecules,
> as it is not at all clear to me that it is possible do this correctly with
> current methods. Perhaps someone else may be able to comment more, but at
> least with long range electrostatics (PME), systems are required to be
> neutral. It IS possible to apply PME to a "charged" system, but I think this
> is typically done by spreading a uniform neutralizing charge throughout the
> box. It isn't clear that this is really correct for FEP/TI, I don't think,
> since in that case you will have a charged molecule overlapping with some of
> the uniform neutralizing charge, which could give strange energy artifacts.
>
> Perhaps things are better if you don't use PME electrostatics, but there may
> be boundary effects.
>
> I need to personally dig in to the literature on this a bit more, but I
> would suggest doing so yourself unless you're very sure that doing FEP/TI
> will give you something meaningful on this system.
>
> Also, if you *do* go that route, I would recommend against slow growth, as
> it tends to be hysteretic. It's probably better to run a bunch of separate
> simulations at different lambda values.
>
> And even further, it is probably *not* a good idea to turn off the charges
> and LJ interactions at the same time. It works better to turn off the
> electrostatics first (without using soft core, as this generally is fairly
> smooth with the charge), and then turn off the LJ interactions using soft
> core (recommend sc-alpha=0.5, as sc-alpha=1.5 is usually too large for LJ).
>
> However, if I were doing it, I would probably try to do it by computing the
> PMF for pulling the zinc ions (or one zinc ion, which is easier) away from
> the protein. You can compute the free energy difference from the PMF. The
> unfortunate thing about this is that it involves sampling a lot of stuff you
> don't care about, but at least it is clear the electrostatics is correct.
> Alternatively, dig into the literature and try and figure out if there is a
> correct way to do the electrostatics in this case. (And please let me know
> what you find out, if you do!)
>
> Oh, and one more thing: If DO compute the free energy by annhilating the
> zinc ions, you probably should use restraints to keep them in a particular
> region as you turn off the interactions, otherwise they will have to sample
> the entire simulation box in order for you to get converged results.
>
> Good luck.
> David
>
>
>
>
>



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