Re: ABF/Steered MD for DNA Hybridization on Carbon Nanotubes

From: Robert Johnson (robertjo_at_physics.upenn.edu)
Date: Tue Jul 03 2012 - 13:47:38 CDT

Hello Everyone,
Are there any best practices for obtaining the average PMF from multiple
runs? I am now using the RMSD to a reference structure as my collective
variable. This has greatly improved the ability of my system to reach the
desired endpoint. However, because DNA is very flexible there are many
different pathways that can be taken to reach the final endpoint. As a
result, each run results in a slightly different PMF with a different value
of the free energy difference between my initial and final states. I have
played around with the fullSamples and width parameters: right now I'm
using fullSamples 1000 and width 0.005A. I think converging on a single PMF
is just not possible in a single run with my system because it is so
flexible. My current plan is to run the calculation several times to get an
idea about the ensemble of PMFs that characterize the system and then just
average them to get "the" PMF for the process. Does this sound like a good
approach? Are there any other things to consider?
Thanks,
Bob

On Thu, Jun 21, 2012 at 10:47 AM, Jérôme Hénin <jhenin_at_ifr88.cnrs-mrs.fr>wrote:

> Hi Bob,
>
> One caveat with the RMSD variable is to use small bins (smaller than
> for a distance, typically). 0.05 A has worked for me in the past, but
> in principle it depends on the ruggedness of the PMF.
>
> Cheers,
> Jerome
>
>
> On 20 June 2012 18:30, Robert Johnson <robertjo_at_physics.upenn.edu> wrote:
> > Hi Jerome,
> > Your idea of using the RMSD sounds like a good one to me. We don't
> expect to
> > get a rigorous result for the PMF - we are more interested in qualitative
> > results. I've never used the RMSD as a collective variable. I see there
> is
> > documentation on how to do this here:
> >
> http://www.ks.uiuc.edu/Research/namd/2.9/ug/node55.html#SECTION0001322150000000000000
> >
> > I also saw that there was some previous discussion on how to do this on
> the
> > mailing list:
> > http://www.ks.uiuc.edu/Research/namd/mailing_list/namd-l/12123.html
> >
> > The user mentions that he is following the tutorial for ubiquitin. I
> found a
> > tutorial here: http://www.ks.uiuc.edu/Training/CaseStudies/pdfs/ubq.pdf
> > However, it seems that the only colvar that is used is the end-to-end
> > distance and not the RMSD. Is there another tutorial available?
> >
> > In the meantime we will try to follow the instructions in the user guide
> and
> > perhaps we can get it to work on the first try. I'm just wondering if
> there
> > are any other caveats that I need to worry about when using this type of
> > colvar.
> > Thanks,
> > Bob
> >
> >
> > On Wed, Jun 20, 2012 at 7:25 AM, Jérôme Hénin <jhenin_at_ifr88.cnrs-mrs.fr>
> > wrote:
> >>
> >> Hi Bob,
> >>
> >> As you've noticed, the coordinate you used so far gives ambiguous
> >> results because your system has a lot of flexibility, and will visit
> >> basins that are not of interest to you. Now there are two kinds of
> >> approaches to this problem:
> >>
> >> 1) add restraints that forbid visiting the unwanted states, but this
> >> changes the meaning of the PMF you are calculating
> >> 2) change your set of coordinates to describe the space of interest
> >> more explicitly, and explore precisely that
> >>
> >> In many cases where you want mostly qualitative information on a
> >> precise process, the first choice is the best one. Trying to extract a
> >> PMF that is quantitative and meaningful and can yield real free energy
> >> differences can be very demanding.
> >>
> >> Now about finding coordinates that describe the process: one simple
> >> coordinate that would discriminate between the states that you mention
> >> is the RMSD of the whole dimer with respect to the hybridized state.
> >> Since the adsorbed state seems to be a deep and broad well, it doesn't
> >> seem to need a very precise description to be visited in the
> >> simulation.
> >>
> >> Caveat: finding good coordinates is difficult for us, because we don't
> >> have the degree of physical intuition that you have about this system,
> >> its degrees of freedom, and what type of motion is relevant or
> >> irrelevant to your problem.
> >>
> >> Cheers,
> >> Jerome
> >>
> >> On 19 June 2012 22:43, Robert Johnson <robertjo_at_physics.upenn.edu>
> wrote:
> >> > Hello All,
> >> >
> >> > I'm interested in determining how two complementary DNA strands can
> >> > hybridize when they are both adsorbed to a carbon nanotube.
> >> >
> >> > I have already performed some ABF calculations to estimate the PMF for
> >> > hybridization. My initial state is shown here:
> >> > http://www.physics.upenn.edu/~robertjo/temp/InitialState.png
> >> >
> >> > My system consists of 2 DNA strands that are each 2 bases long - in
> this
> >> > case each strand is GC. The blue bases are forming a G-C base pair.
> Over
> >> > the
> >> > course of the simulation I constrain the distances between the H-bond
> >> > donors
> >> > and acceptors for this base pair. Therefore, the blue base pair is
> >> > present
> >> > throughout the entire simulation.
> >> >
> >> > Then ABF is employed to force the two red bases to come together. The
> >> > collective variable used is the distance between two atoms that share
> a
> >> > H-bond when the red bases are paired (the orange atoms). Applying ABF
> >> > causes
> >> > (in most cases) the red bases to move toward each other and to form a
> >> > base
> >> > pair. The only way the red bases can hybridize is by lifting off the
> >> > surface
> >> > of the nanotube. The final state is is shown here:
> >> > http://www.physics.upenn.edu/~robertjo/temp/Hybridized.png
> >> >
> >> > A graph of a representative PMF of this process is shown here:
> >> > http://www.physics.upenn.edu/~robertjo/temp/RepresentativePMF.jpg
> >> >
> >> > The 2 strands initially start off in a deep energy minimum
> corresponding
> >> > to
> >> > adsorption to the nanotube. Forcing the two red bases to hybridize
> >> > requires
> >> > the system to surmount a large energy barrier. Then the system falls
> >> > into a
> >> > small energy minimum as the bases hybridize.
> >> >
> >> > About 60% of the time, I obtain a similar structure (and PMF) to that
> >> > shown
> >> > in the image(s). However, the rest of the time the bases come together
> >> > in an
> >> > orientation that does not favor hybridization. This makes it a little
> >> > bit
> >> > difficult to analyze the results since it is not known ahead of time
> >> > what
> >> > pathway the molecules will take.
> >> >
> >> > DNA is very flexible and I doubt that I will be able to fully sample
> all
> >> > the
> >> > different pathways that the DNA takes to reach the hybridized state.
> >> > However, I would like a more reliable method for forcing the system to
> >> > reach
> >> > this hybridized state.
> >> >
> >> > Does anyone have ideas for better collective variables to use? Would a
> >> > different method (i.e. metadynamics or steered MD) be a better choice?
> >> > Since
> >> > I'm interested in a very specific final state, I've also considered
> >> > starting
> >> > the simulation from the hybridized state and forcing the strands
> apart.
> >> >
> >> > I would appreciate any feedback you could give. Thanks!
> >> > Bob
> >> >
> >> > --
> >> > Bob Johnson, PhD
> >> > Lab Coordinator & Lecturer
> >> > Department of Physics and Astronomy
> >> > University of Pennsylvania
> >> > 209 S. 33rd St.
> >> > Philadelphia, PA 19104
> >> > Office: David Rittenhouse Laboratory 2C11
> >> > Phone: 215-898-5111
> >> > http://www.physics.upenn.edu/~robertjo
> >
> >
> >
> >
> > --
> > Bob Johnson, PhD
> > Lab Coordinator & Lecturer
> > Department of Physics and Astronomy
> > University of Pennsylvania
> > 209 S. 33rd St.
> > Philadelphia, PA 19104
> > Office: David Rittenhouse Laboratory 2C11
> > Phone: 215-898-5111
> > http://www.physics.upenn.edu/~robertjo
>

-- 
Bob Johnson, PhD
Lab Coordinator & Lecturer
Department of Physics and Astronomy
University of Pennsylvania
209 S. 33rd St.
Philadelphia, PA 19104
Office: David Rittenhouse Laboratory 2C11
Phone: 215-898-5111
http://www.physics.upenn.edu/~robertjo

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