Re: Umbrella Sampling plus restraints

From: Aron Broom (broomsday_at_gmail.com)
Date: Fri Jul 20 2012 - 08:48:00 CDT

good luck with it! 1 microsecond certainly is a long time. You might
consider multiple replica metadynamics as a method. It will allow for
excellent scaling much as many umbrella sampling windows would, but may be
simpler and explore the reaction coordinate more efficiently.

~Aron

On Fri, Jul 20, 2012 at 5:44 AM, felmerino_at_uchile.cl <felmerino_at_uchile.cl>wrote:

> Hi aron,
>
> >> If you apply this restraint, it will not change the manner in which you
> generate the PMF, that is, you will still only use your reaction coordinate
> forces and harmonic centers as input to WHAM with the data for the reaction
> coordinate trajectory over that window.
>
> I know that people actually do the WHAM in this manner but in principle
> you just need the total bias energy whixh is in the restraint potential in
> most cases but not necessarily. Think for instance in the case when you do
> this with temperature, then you do a 2D histogram of potential energy and
> reaction coordinate. In the same fashion i can add the umbrella energy plus
> the base restraint energy to have the total bias energy of the microstate
> and then histogram those energies and my original reaction coordinate.
>
> Anyhow, i just decided to extend the DNA a couple of bases to not
> interfere with my calculation. As we are trying to model DNA binding to a
> promoter the opening is physically unrealistic since this is a side effect
> of truncating the DNA. Bases DO open when they are in the end, but the DNA
> should not end up there in the first place.
>
> Regarding a 2d with the H-bond, it is not an option since this calculation
> already requires close to a microsecond and the second dimention seems to
> be very irrelevant for the process.
>
> Regarda
>
>
>
> Felipe
>
> ----Mensaje original----
> De: broomsday_at_gmail.com
> Fecha: 18-jul-2012 9:47
> Para: "felmerino_at_uchile.cl"<felmerino_at_uchile.cl>
> CC: <namd-l_at_ks.uiuc.edu>
> Asunto: Re: namd-l: Umbrella Sampling plus restraints
>
>
> Hi Felipe,
>
> If you apply this restraint, it will not change the manner in which you
> generate the PMF, that is, you will still only use your reaction coordinate
> forces and harmonic centers as input to WHAM with the data for the reaction
> coordinate trajectory over that window.
>
> This doesn't mean, however, that your restraint might not change the PMF.
> The "real" PMF (at least as far as the forcefield is concerned), is the one
> where there are no extra restraints, but, that assumes that you have
> sampled long enough to get good coverage of all the relevant microstates.
> So in your case with the base opening, the particular windows of the
> reaction coordinate in which you see this happening might need to be
> sampled for longer.
>
> One problem I would say about your wanting to add the restraint is, what
> reason do you have for believing the base DOESN'T open up? Do you trust
> (to a reasonable extent) the forcefield parameters for the DNA? If so,
> then the base must be opening up because there is a more favourable
> interaction with the protein, and restraining it may give a false result on
> the PMF where your binding appears weaker, or the activation energy higher,
> than it really is.
>
> Something you might try is 2D Umbrella sampling, in which the second
> reaction coordinate is a distance or H-bonding or something for that
> base-pair, then you could see if the lowest free energy path for separation
> of your DNA-protein complex involves a movement of that base. If you don't
> have a good reason for believing that base is entirely non-dynamic, then I
> would suggest you might have found a rather interesting "gate-keeping"
> element on your reaction path.
>
> Anyway, something I would highly recommend is to use MetaDynamics
> initially to look at this. It is far easier to setup than Umbrella
> Sampling, requires less manual intervention (deciding on new force
> constants and centers) and generally give a good rough idea of the PMF much
> faster, not to mention that extending it to 2D (2 reaction coordinates) is
> trivial, whereas Umbrella Sampling in 2D can be taxing. You can then use
> that metadynamics bias in a static way and perform Umbrella Sampling on top
> of it in order to refine the PMF and get error bars.
>
> ~Aron
>
> On Wed, Jul 18, 2012 at 8:18 AM, felmerino_at_uchile.cl <felmerino_at_uchile.cl>wrote:
>
>>
>> Dear all,
>>
>> We are working currently in some free energy calculations on a protein
>> DNA complex using unbrella sampling with the minimal distance between the
>> two molecules as the rea_ction coordinate. Everything goes OK except that
>> the last base pair in the DNA opens from time to time and contacts the
>> protein. We would like to restrain it in order to maintain the watson-crick
>> pairing but we don't know if it would do any harm to the PMF. As we are
>> using tcl forces we know exactly how much energy the bias is applying to
>> the system so in principle the should be no mixing between the pulling
>> restraint and the bais pairing restraint.
>>
>>
>> We were then wondering if somebody can point to anything against this
>> approach. Also, i am not sure now if we need to use only the bias energy
>> for the unbrella restraint or it is better to add the ones from the bases
>> restraint in order to do the histograming as well. In principle, i think
>> you need to add all the extra energy added to obtain every particular
>> microstate, but i am not sure.
>>
>>
>> Any ideas?
>>
>>
>> Regards
>>
>>
>> Felipe
>>
>
>
>
> --
> 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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