Diffusion along the US order parameter, computed from US, is almost always
going to over-estimate the diffusion rate if there are any hidden free
energy barriers (i.e., dG barriers orthogonal to your US order parameter),
which there very often are. It's likely that the dehydration cost of those
two zwitterionic groups on your solute is higher than the cost to deform
the bilayer and allow hydration of your solute while it's near the bilayer
center. If that's true, then you're going to run into the common orthogonal
barrier near the bilayer center which involves flipping the hydrating
defect from one side of the bilayer to the other. Your US dG profile and
diffusion tell you nothing about this so you will underestimate the mean
time required to cross the bilayer.
Chris.
On Thu, Apr 6, 2017 at 1:01 PM, FabrÃcio Bracht <fabracht1.gmail.com> wrote:
> Hi.
> I've been doing umbrella sampling simulations of a molecule going across a
> POPC bilayer and would like to ask a few questions. First let me describe
> what I've done so far. I'll be discussing about only one of the molecules
> I've worked on, since all others follow the exact same protocol.
> First I generated a lipid bilayer using CHARMM gui. Then I inserted the
> molecule in substitution from a couple of water molecules. Then I ran
> minimization, heating, equilibration using the the amber lipid tutorial as
> a guideline. After that, I ran 250 ns of equilibration. My membrane is
> composed of 120 POPC molecules. The crossing molecule is the
> 5-methyl-2,4-dinitrophenol. When I started this work, I found this tutorial
> online :
> https://github.com/callumjd/AMBER-Umbrella_COM_restraint_
> tutorial/blob/master/README.md
> Which was very useful. I would like to take this opportunity to thank
> Callum Dickson for the tutorial and discussion within. Ok, so, moving on.
> The tutorial also listed 2 very interesting papers.
> http://pubs.acs.org/doi/abs/10.1021/ct2009208 and
> http://pubs.acs.org/doi/abs/10.1021/ct200316w
> And so, I decided to extract the umbrella windows from the 250ns
> simulation, and not from a pulling simulation, as was my plan earlier.
> I extracted 150 z position frames, according to the distance between the
> COM of the molecule and the COM of the POPC nitrogens. These ranged from
> -35 to +35 angstrom. I then set the 150 distance restrain files spacing
> them equally using numpy.linspace. You might be wondering why I chose 150
> and not 140. Well, you see, there was some slight miscalculation regarding
> the size of the simulation box. The original idea was to use 0.5 angstrom
> spacing and the original box (from charmm gui) would give me a range from
> roughly -37.5 to +37.5.....so...continuing...
> I ran about 30 ns of equilibration with a z-position restrain for each
> window (some windows required more time and some required less). After that
> I ran 15 ns of production run (using the same z-restrain). Then I checked
> if the distance distribution histograms overlayed (nice overlay, indeed). I
> spaced the distout file samples every 10 md steps. I discarded the first 5
> ns and performed wham on the last 10 ns using positions from z axis only.
> I used different block sizes (within the 10ns production window) in order
> to check for convergence, using the final PMF as the convergence parameter.
> I am not sure that this is the best convergence criteria, but I was able to
> see that windows larger than 3 ns had an average PMF that differed very
> little (less than 0.01 for some z-points). This was a bit time consuming,
> but it enabled me to have some idea about the accuracy of the final PMF.
> Ok, now it comes to what I really wanted to discuss. Within the tutorial,
> there are a few scripts that enabled me to calculate the diffusion and
> permeability coefficient of the molecule.
> The problem is that the final value I get for the permeability coefficient
> is a bit large (for my taste, at least). And I was wondering If I did
> anything wrong. I get as final results,
> Reff: 0.0620777958588 Peff: 16.1088193639 cm/s
> If you like, I can gladly share any data you need.
> I'm not sure if I can attach graphs here, I'll try anyway. The first one
> should be the diffusion coef values in cm^2/s. The second should be the
> PMF. Note that it is not perfectly symmetrical because I used the entire
> z-coordinate across the membrane in order to calculate it. I thought about
> averaging the two halves and mirroring it, like Callum did in the tutorial,
> but though about asking someone first.
>
> Thank you
> FabrÃcio Bracht
>
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Received on Thu Apr 06 2017 - 12:30:04 PDT
