Hi Adrian.
So, one problem would be how to define the boundary between constant pH and
constant protonation. Maybe by analyzing the umbrella windows with hydrogen
bonds between the molecule and water, I can get a good idea where the
boundary is. What do you think?
I ran two test windows in order to see the effect of being inside the
membrane on the populations. The first window has the molecule stuck in
water and the second has the molecule right in the middle of the membrane.
I chose to run both simulations with pH = pKa. I guess that this way the
effect on the populations would be more visible.
Up until now there seems to be a slight difference in protonated fractions
from 0.449 in water to 0.566 inside the membrane. Not as much as I had
expected, but still, a difference.
Fabrício
2016-12-15 12:01 GMT-02:00 Adrian Roitberg <roitberg.ufl.edu>:
> Hi Fabricio,
>
> I concur with Jason's comments, but as it turns out, it might not be as
> bad as it looks.
>
> The constant pH as is would 'work' but the results might be suspect. The
> discussion on the literature about this problem seems to be if a
> molecule that is charged in water, goes across as neutral (hence the
> constant pH), OR if it brings some water inside with it and stays
> charged. Arginines for instance seems to NEVER unprotonate and they
> bring a water posse with them across the membrane.
>
> A lot of data suggests that if a charged molecule become neutral to
> cross the membrane, then it does do right at the water/membrane
> interface, so once inside the non polar section, it never really changes
> protonation states. If this is true, one could do constant pH from water
> up to the interface, and then do constant protonation while inside the
> membrane.
>
> This is all very tricky and of course subject to lots of validation!
>
> adrian
>
>
> On 12/15/16 7:58 AM, Fabrício Bracht wrote:
> > Hi Jason. When you say treat the lipids themselves as solvent, do you
> mean
> > to include them as titratable residues? I didn't quite get what you
> meant.
> > Is the Stern's paper you are referring to this one?
> > http://aip.scitation.org/doi/abs/10.1063/1.2731781?journalCode=jcp
> > I don't have access to the full paper, but thanks anyway for the
> reference.
> > We don't have a charmm's license also.
> > Guess I'll have to see how the results come out.
> > Thank you
> > Fabrício
> >
> > 2016-12-15 2:22 GMT-02:00 Jason Swails <jason.swails.gmail.com>:
> >
> >> This is a very challenging problem, and probably not one that the
> explicit
> >> solvent method in Amber is well-equipped to handle.
> >>
> >> However, as long as you don't treat the lipids themselves as solvent
> (i.e.,
> >> they are included in the protonation state change attempts), it's
> >> *possible* that the results might be reasonable.
> >>
> >> However, purely explicit solvent models will almost certainly be better
> >> here (e.g., the approach inside CHARMM or Stern et al.'s method for
> >> discrete protonation states).
> >>
> >> HTH,
> >> Jason
> >>
> >>
> >> On Wed, Dec 14, 2016 at 6:49 PM, Fabrício Bracht <fabracht1.gmail.com>
> >> wrote:
> >>
> >>> Hi. I am calculating the PMFs of molecules going across a POPC membrane
> >>> using umbrella sampling. Up until now, we've worked only with molecules
> >>> with no titratable groups. But there are some molecules that do have
> >>> titratable groups (carboxylates and amines mainly). Being so, I thought
> >>> that I could use CpHMD to get the correct protonation state while going
> >>> across the membrane. But then I realized that there are some problems
> >>> related to that. I would like to hear your comments on them.
> >>> First: If I do parameterize the charges and the free energy in order to
> >>> reproduce the pKa in water (explicit), although I may have a correct
> >>> protonation distribution when the molecules are still outside the lipid
> >>> bilayer (i.e. still in water) I will probably won't have that once they
> >> are
> >>> inside the bi layer mainly due to the fact that the actual exchange of
> >>> protonation states is still done using the dielectric constant of water
> >>> using implicit solvent.
> >>> Second: Since pH is valid only in water. It would make sense to sample
> >>> different protonation states once inside the membrane. So, if I were to
> >>> sample the protonation states, It would make more sense to do while
> still
> >>> in water and maybe in the region near the polar PC groups.
> >>> Actually, I had more questions on the matter, but I thought about maybe
> >>> starting with these two and see how you guys respond.
> >>> If possible, I would very much appreciate some suggestions on the
> matter.
> >>>
> >>> Thank you in advance
> >>> Fabrício
> >>> _______________________________________________
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> >>> http://lists.ambermd.org/mailman/listinfo/amber
> >>>
> >>
> >>
> >> --
> >> Jason M. Swails
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> >>
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> --
> Dr. Adrian E. Roitberg
> University of Florida Research Foundation Professor.
> Department of Chemistry
> University of Florida
> roitberg.ufl.edu
> 352-392-6972
>
>
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Received on Thu Dec 15 2016 - 07:00:02 PST
