[gmx-users] Re: FEP softcore problematics

[David Mobley]

Matt,


> After previous discussions that suggested separating vdw and charge mutations, I thought
> it was literally a 2 stage process. In one stage I modify all charges (including those
> for disappearing atoms going to zero) from their starting values to their final values,
> using 10 lambda points and no soft cores. In another stage I modify vdw parameters from
> their A states to their B states with soft cores, using only the final charge values for
> A and B states, over 21 lambda points. My statistical error is enormously reduced from
> when I was trying to modify charges and vdw simultaneously, but the results I'm getting
> are still a bit puzzling.

Sorry about all of the confusion. Basically, the answer to this
depends on what exactly you're doing. (I should really write all of
this up in a tutorial soon). The way I think about it is that there
are two fundamental principles you need to keep in mind, and you can
do it any way you can cook up as long as you follow these two:
(1) Always use soft core when modifying vdW interactions
(2) Never leave charges on atoms for which you are turning off the vdW
interactions

The corollary is that you should generally not change charges and LJ
interactions at the same time, but this is more for efficiency reasons
than anything else.

So, if you can cook up a way to do what you want that doesn't violate
principles (1) or (2) and only involves two steps, great. For my
purposes, I'm doing absolute binding free energy calculations where I
don't mutate one thing into something else, so I can always do this --
I'm just disappearing atoms, so I first turn off teh charges, and then
second turn off the LJ interactions.

More generally, I suppose if you can think of a way to do the
transformation you want that only involves either (a) inserting atoms,
or (b) deleting atoms, but not both, you can do it in two steps. If it
only involves insertion, you first modify the LJ interactions to
"appear" some dummy atoms, and then turn on their charges. If it only
involves deletion, you first turn off the charges, then you turn off
the LJ interactions. If it involves both insertions and deletions,
maybe there is a way to do it in only two steps, but it isn't obvious
to me.

> It sounds as if I should actually be running 3 series of calculations -- is this
> correct? I can:
>
> 1) Neutralize any atoms which are being disappeared
> 2) Modify LJ interactions from A state to B state
> 3) Change charges to final charges for B state.
>
> or I can:
>
> 1) make the charges of the atoms present in the A-state go to those of the B-state
> 2) change the LJ of the A-state to the B-state.
> 3) make the charges of the atoms present in the B-state go to those of the B-state.
>
> In the first series of calculations, there is one series of charge mutations that simply
> changes the charges to 0 on disappearing atoms. The LJ interactions are changed while
> atoms that will disappear are already set to 0 charge while atoms that do not disappear
> continue to hold their starting charges. In the final series of calculations, atoms that
> did not disappear in the B state are changed toward their final charges while the ending
> state LJ parameters are used. Is this correct? I want to make sure I am not
> misinterpreting anything.
>
> In the second, equivalent series of calculations, the first job is to make all A-state
> charges go to B-state charges. This would include both atoms that disappear and those
> that do not disappear but that change parameters. The second job is to change the LJ
> parameters from A-state to B-state while using... the B-state charges, I presume? I
> thought that disappearing atoms shouldn't be charged as their LJ parameters change.
> Under this interpretation, I'm not sure what the 3rd part means. I thought B-state atoms
> already underwent mutation to B-state charges.

Now that you mention it, I'm not entirely certain I understand Berk's
scheme (it makes me confused, too). I still think the most
straightforward one is my scheme: First neutralize any atoms which are
disappearing; second, change the LJ parameters (either for insertion
or deletion); third, modify all of the remaining charges to get where
you want to end up at.

David


> Matt Ernst
> Washington State University
>
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