Re: PMF with ABF for ion channels in a spherical molecule

From: Aron Broom (broomsday_at_gmail.com)
Date: Tue Jun 28 2016 - 16:37:49 CDT

Yes, the simple equilibrium simulation wouldn't be usable unless you had
complete transit, ideally many times, such that you could construct a
reliable histogram of the population density at each position along your
reaction coordinate.

For ABF, yes this is certainly possible. If you just use the distance from
the center of the ferritin, you wouldn't need the orientation restraint,
and you could try the whole thing without any other restraints. You might
also think of trying meta-dynamics or well-tempered metadynamics, which are
both available within NAMD.

In general, I would suggest the following two things to look out for:

1) Do the biasing simulation twice starting from some different initial
snapshot, and see how reproducible the PMF is.

2) If the energy values along the PMF seem extremely high (like energy
barriers of hundreds of kcal/mol) it is likely that the simulation needs to
be run for longer in order to better equilibrate (what that means in terms
of the parameters for a given biasing method is different). I think
realistically you will need to have at least 100 ns of biased simulation
time to get a reliable answer, and maybe more (maybe even much more).

On Tue, Jun 28, 2016 at 5:20 PM, Olya Kravchenko <ovkrav_at_gmail.com> wrote:

> Hi Aron,
>
> thanks a lot! I want to do both: set up a new simulation to obtain PMF
> via ABF as well as analyze the one I already have. I just was not sure
> if it is at all usable for PMF, particularly because I do not observe
> ions leaving the channel (but I see progression through other binding
> sites, they just get stuck at the last one).
>
> Olga
>
>
>
>
>
> On Tue, Jun 28, 2016 at 4:57 PM, Aron Broom <broomsday_at_gmail.com> wrote:
> > Hi Olga,
> >
> > For the orientation restraint, the protein will rotate just because of
> > random thermal motion and interaction with the solvent.
> >
> > I had thought you were thinking of setting up some kind of biased
> > simulation, like umbrella sampling, adaptive bias force, or something
> else.
> > But it sounds like you just want to do the analysis of an existing
> > simulation. In that case no restraints are needed.
> >
> > If you think that you have something useful in your 20 ns simulation and
> you
> > are hoping to just analyze it along a single reaction coordinate to
> generate
> > a PMF, then I think you could just use the distance from the ion to the
> > center of mass of the whole ferritin.
> >
> > I have never done ion transport simulations, but I would be surprised if
> 20
> > ns was long enough to see enough transits to get good statistics for a
> PMF.
> >
> > ~Aron
> >
> >
> > On Tue, Jun 28, 2016 at 4:35 PM, Olya Kravchenko <ovkrav_at_gmail.com>
> wrote:
> >>
> >> Hi Aron,
> >>
> >> thank you for replying!
> >>
> >> My system is ferritin, it is a spherical molecule that is empty inside
> >> (such as soccer ball). The ions go inside through channels in the
> >> surface, there are 8 channels, each consists of three chains. I am
> >> trying to implement your suggestion now, i.e. align one of the
> >> channels with Z axis.
> >>
> >> For the harmonic restraint, what exactly should be restrained? I read
> >> the manual about orientation variable, but I don't quite understand
> >> what happens if I do not use it. The manual says it is needed to stop
> >> the rotation of the protein. Why would it rotate?
> >>
> >> Another thing: I recently ran a 20 ns simulation (I set it up without
> >> PMF in mind at the time), so I now have a trajectory and roughly
> >> identified ion pathway, but none of the channels are aligned with Z
> >> axis. Do I understand it correctly that I cannot use the results for
> >> obtaining PMF along the axis of the channel? Is there a conversion
> >> that would allow me to utilize the current trajectory? (this is why I
> >> thought about abscissa first).
> >>
> >> Thank you,
> >>
> >> Olga
> >>
> >>
> >>
> >>
> >>
> >>
> >> On Sun, Jun 26, 2016 at 4:13 PM, Aron Broom <broomsday_at_gmail.com>
> wrote:
> >> > I don't think I fully understand what your system looks like.
> >> >
> >> > But assuming it is some kind of continuous channel or pore, you can
> use
> >> > the
> >> > DistanceZ collective variable, and align the channel along Z. Then
> you
> >> > would also use the Orientation collective variable with a harmonic
> >> > restraint
> >> > to keep your spherical molecule's channel aligned with the Z-axis.
> >> >
> >> > In terms of having a longer distance, that would depend. If you only
> >> > cared
> >> > about being longer in one direction, you could define the reaction
> >> > coordinate as DistanceZ between the ion and the center of mass of
> atoms
> >> > at
> >> > the channel entrance. If you wanted to get extra PMF information in
> >> > both
> >> > directions, then I think you would need to use the dummy atom
> >> > functionality
> >> > of the collective variable module to define a dummy atom at some
> >> > particular
> >> > Z coordinate that would be before the channel entrance.
> >> >
> >> > On Fri, Jun 24, 2016 at 6:01 PM, Olya Kravchenko <ovkrav_at_gmail.com>
> >> > wrote:
> >> >>
> >> >> Hi all,
> >> >>
> >> >> I am trying to figure out how to calculate PMF for ion channels in a
> >> >> spherical molecule. I would like to use position of the ion along the
> >> >> channel axis as the reaction coordinate. How does one define the
> >> >> reaction coordinate for a radial channel in a sphere?
> >> >>
> >> >> At this moment I can only think of defining it via abscissa and use
> >> >> centers of mass of the atoms at the entrance and exit of the channel.
> >> >> But then residues there move, would that affect the reaction
> >> >> coordinate? Also, if I want the distance to be longer than the length
> >> >> of the channel, how would I define that within abscissa?
> >> >>
> >> >> I would appreciate your input.
> >> >>
> >> >> Olga
> >> >>
> >> >
> >> >
> >> >
> >> > --
> >> > Aron Broom M.Sc
> >> > PhD Student
> >> > Department of Chemistry
> >> > University of Waterloo
> >
> >
> >
> >
> > --
> > Aron Broom M.Sc
> > PhD Student
> > Department of Chemistry
> > University of Waterloo
>

-- 
Aron Broom M.Sc
PhD Student
Department of Chemistry
University of Waterloo

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