Re: 2.7b metadynamics ::alpha module :: folding of a single helix in water

From: Ali Emileh (ali.emileh_at_gmail.com)
Date: Wed Jul 22 2009 - 21:18:11 CDT

Dear Giacomo,

Thanks to your help, I finally folded the helix. Although
I didn't use the same colvar (alpha).

I tried using the alpha colvar with a couple of different HillWeight
(changing stepwise, almost an order of magnitude from 0.04 to 0.5)
but wasn't able to fold the helix within the 10 ns time frame
I was hoping for. So next I tried your other suggestion to
use harmonic steering as a works/not works solution. I
tied the same atoms to the harmonic restraint with a
forceConstant of 10 (colvar width was set to 0.05) and
put a lowerWallConstant of 200 on
the lowerBoundary (0.3; the colvar starts at 0.445). Center
of the restraint was set to 0.5 and I asked NAMD to drive
the colvar to 1.0. During the first 5000 steps, the colvar
goes down and past 0.3 and then stays below that (due
to the wall? but why did it pass the wall in the 1st place?) for
the whole duration of the simulation and somehow
stabilizes around 0.2. Looking at the DCD, I can somewhat
see the partially folded helix being a bit unfolded after
the 10 ns run. Here's my config file:

=====
colvarsTrajFrequency 1000

colvar {
    name a1
    width 0.05
    outputVelocity on
    outputAppliedForce on
    #outputSystemForce on
    lowerBoundary 0.3
    upperBoundary 1.0
    lowerWallConstant 200

    alpha {
        residueRange 100-116
        psfSegID G
    }
}

harmonic {
    colvars a1
    forceConstant 10
    centers 0.5
    targets 1.0
    targetsNumSteps 2450000
}
=====

Now I have been able to fold this excised helix using
TMD and in the context of its parent protein before,
albeit using much much larger force constants, within
>5 ns and don't know why it's not working here. Maybe
I'm not using enough force? Also why is that the peptide
passes the lowerWall? I'll try to repeat this run with a
larger force constant some time later.

As with metadynamics :
I used metadynamics with hillWieght of 0.5 and
newHillFrequencies of 100 (default) on different colvars:
* 2 independent dihedral colvars, one representing all the
psi angles of the backbone and the other, all the phi
angels (obviously with a lot of overlap in the two colvars),
no walls.
* 2 independent colvars of hBond and distance, again
between all the target atoms (e.g. hbonds of NH1.109-O.105
and distance between the same atoms). no walls.

No results from the above two colvars.

My first -unintelligent!- guess would be to combine the
independent colvars linearly into one large one and apply metadynamics
to that, but is it possible to do so with colvars of different type
and what would be the boundaries? Plus, I can't
physically imagine the end result of such a combination (even
a multi-dihedral colvar) when you look at the PMF vs. colvar
graph.

Next I tried the RMSD colvar. To my delight, this one worked
and successfully folded the helix. My first shot with 0.04
hillWeight and newHillFrequencies of 10 failed but I reduced
the frequency to 100 (default) and increased the Weight to
0.5 and this folded the peptide into a helix within the 10 ns
frame I wanted and gave me a PMF. I changed these values
based on your comment: "...by the time you've added energy
to one structure metadynamics has moved it back to a similar
one?" which I didn't quite understand. Isn't it that you add the
Gaussian to your potential function, wait for newHillFrequency
steps and add another one? Why should metadynamics move
it to a similar one? small hills?! Can you please kindly clarify this?

Looking at the end results and the system and applied forces
of the output, I guess the units are kcal/mol/A (when using
the RMSD covlar) for the applied forces, right? Do the system
forces have the same units? Is it normal to observe system forces
of 5-20 times larger than the biasing (applied?) forces?
Also, the .pmf file outputs the pmf as a function of the colvar,
right? I just want to make sure that I got the basics right.

Again, thank you very much for all your time and patience. In
reporting the other tried and failed results, I thought that (in
addition to me) maybe someone else may benefit from them
later.

Cheers,
Ali

On Wed, Jun 10, 2009 at 9:57 AM, Giacomo Fiorin <gfiorin_at_seas.upenn.edu>wrote:

> Hi Ali, I see: what you mean (narrowing a1 to an interval of interest) is a
> good idea, but to do so you also need to set some force constants at
> the two boundaries. Otherwise, those are just the limits of the grid, and
> they get expanded over time as the colvar moves outside of them. The
> fact that lowerBoundary goes negative can be worrisome, but it is only
> due to the
> fact that the code managing the grid doesn't know that a1 can't go
> negative, and allocates a buffer region.
>
> Of course, it's never 100% guaranteed that the code is free of bugs,
> especially at this stage. So, if you do observe negative values of
> the alpha variable in the .colvars.traj file, I'd like to know.
>
> You're applying small hills (0.04 kcal/mol) but very frequently (10
> steps), so you *are* pumping energy into it. Maybe the helix is just
> too stiff and by the time you've added energy to one structure
> metadynamics has moved it back to a similar one?
>
> This is why I suggest that you try the harmonic steering: you could,
> say, set a target of 1 to try and fold the helix completely. Unlike
> in metadynamics, at least you'd drive it monotonically there, and
> you'd have to cope with less complications.
>
> Otherwise, if your target is the folded helix, and the other
> structures are not relevant to you, it may simply be happening that
> because of the system's nature the colvar does not respond as quickly
> as you want it to, because other degrees of freedom need to be forced
> (i.e. additional colvars).
>
> Ciao
> Giacomo
>
> ---- ----
> Giacomo Fiorin
> Center for Molecular Modeling at
> University of Pennsylvania
> 231 S 34th Street, Philadelphia, PA 19104-6323
> phone: (+1)-215-573-4773
> fax: (+1)-215-573-6233
> mobile: (+1)-267-324-7676
> mail: giacomo.fiorin_<at>_gmail.com
> web: http://www.cmm.upenn.edu/
> ---- ----
>
>

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