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

From: Olya Kravchenko (ovkrav_at_gmail.com)
Date: Fri Jul 01 2016 - 15:50:15 CDT

Hi Aron,

thanks a lot, this is very helpful!

I ran my simulation a few nanoseconds longer and saw ion exiting the
channel, but only in cases where I already had one or two ions in the
channel to start with and only after more ions entered the channel. It
took ~14ns.

Now I would like to do single ion PMF with Z as reaction coordinate
and for that I am setting up another simulation where one of the
channels is aligned with Z.

Here is what I don't understand. For single ion PMF using ABF method,
do I have to run a really long trajectory that shows ion passing all
the way through the channel (with the purpose of using the snapshots
to define subsequent ABF windows)? Or should I equilibrate my system,
then physically place ion in the next subsequent window, equilibrate
it, then use result as initial configuration for the next window and
so on? I am not sure I understand the process correctly.

And another thing, if I understand it correctly, there should be only
one ion in the channel and no ions within certain distance from the
ion that I follow. What if other ions approach during simulation? Is
there a way to keep them at certain distance?

Olga

On Tue, Jun 28, 2016 at 5:37 PM, Aron Broom <broomsday_at_gmail.com> wrote:
> 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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