From: Giacomo Fiorin (giacomo.fiorin_at_gmail.com)
Date: Mon Mar 25 2013 - 17:11:29 CDT
Well-tempered metadynamics is available in regular NAMD, at least in the
CVS - nightly build version.
Giacomo
On Mon, Mar 25, 2013 at 6:06 PM, Niklaus Johner <nij2003_at_med.cornell.edu>wrote:
> Yes I agree with all your comments.
>
> The comment about multidimensional problems is of course very important.
> As a rule of thumbs, I'd say 2D pmfs are usually still feasible, 3D will
> mostly require too much sampling.
>
> For metadynamics vs ABF, I was probably thinking of well-tempered
> metadynamics (also not available in namd, but in plumed), which will
> explore only the regions with lower free-energy (the barriers that can be
> crossed will depend on the chosen parameters). This can be an advantage or
> a disadvantage, depending on what you want to do. Typically well-tempered
> metadynamics should give you better sampling of the low free-energy states,
> but less sampling in the rest (I have never actually done that
> comparison!). So your estimates of barriers might be worse, although the
> estimates of free-energy difference between the most probable states
> better, than with metadynamics.
>
> Best,
>
> Niklaus
>
>
> Niklaus Johner
> Weill Cornell Medical College
> Harel Weinstein Lab
> Department of Physiology and Biophysics
> 1300 York Avenue, Room D-501
> New York, NY 10065
>
> On Mar 25, 2013, at 5:43 PM, Aron Broom wrote:
>
> I think Niklaus' synopsis is excellent. I would say though that I think
> metadynamics and ABF are fairly similar in their exploration. Metadynamics
> does initially sample the lower energy regions, but as the simulation
> progresses and those flatten out you move towards more uniform sampling.
>
> The other thing I would add to these specific points is that a method like
> metadynamics is easily expanded to an N-dimensional reaction coordinate
> (although the amount of sampling required to explore this properly may make
> it irrelevant in many cases) whereas I think this is more challenging for
> many of the other methods. That being said, an additional point to what
> Niklaus mentioned, is that while in theory you can just continue a
> metadynamics or ABF run until it properly converges, if you've chosen
> parameters you later realize where poor choices (e.g. bin widths for the
> resolution of your PMF, too few samples for ABF, or too high of hills for
> metadynamics), you will still most likely end up restarting the whole
> thing. With umbrella sampling, however, you can always continue to
> simulate and never worry that anything is a complete waste.
>
> On the note of umbrella sampling and convergence, it's probably best
> practice for each window to start from a set of coordinates you think are
> different from what that window's equilibrium configuration will look like
> and run two different simulations with differing random variables
> (langevinThermostat for instance) and only use the portions of the
> simulations that are identical (e.g. after the two different simulations
> have converged upon one another) in your analysis. It means more
> simulating, but it also means you can be more confident that you don't have
> the wrong answer because of a slow degree of freedom creating a large
> energy barrier as Niklaus mentioned.
>
> ~Aron
>
> On Mon, Mar 25, 2013 at 5:17 PM, Niklaus Johner <nij2003_at_med.cornell.edu>wrote:
>
>> I have tried out several methods for several different problems over the
>> last year, but my experience is still limited. I'll nevertheless give you
>> my opinion. I'll won't consider the alchemical transformations here (FEP,
>> thermodynamic integration,...)
>>
>> First of all I think SMD has a disadvantage over all the others. Namely
>> if you don't pull slowly enough, you will largely overestimate the force
>> and you won't have any way of increasing the sampling except restarting the
>> simulation with a smaller pulling speed. With most other methods, if your
>> free energy is not converged you can simply continue your simulation.
>>
>> Now in my experience, using SMD for non-equilibrium simulations and the
>> Jarzynski type of equalities to calculate free energies doesn't work too
>> well. I was calculating the binding free energy of a peptide to a membrane,
>> but the friction of the water on the peptide would lead to large
>> overestimates of the free energy. Better go for a very slow pulling force
>> and very few repeats.
>>
>> Umbrella sampling seems to be a very safe bet in many cases. The main
>> drawback is when using a CV that is highly degenerate (multiple states for
>> a single value of the CV) and for which the energy barriers to interconvert
>> from one state to the other at that particular value of the CV are large.
>> Then you will basically be highly biased towards the starting structures
>> that you use in each window. Think of the folding of a peptide, described
>> by the radius of gyration for example, where it might be very difficult to
>> interconvert between two distinct folded states without going through an
>> unfolded state (large radius of gyration). In such cases methods like
>> metadynamics or ABF, where you will cross the whole range of the CV many
>> times will be more appropriate.
>>
>> For ABF and metadynamics, I think that a major difference is that in
>> metadynamics you will mainly sample the low free energy regions, whereas in
>> ABF you will get a more homogeneous sampling of the whole CV space.
>> Metadynamics has the disadvantage of offering (to my knowledge) no real
>> error estimate.
>> Another method similar to metadynamics but where error estimates are
>> straightforward, and allows for multiple totally independent simulations is
>> "driven adiabatic free energy dynamics". This is nevertheless not available
>> in namd but is included in the plumed plugin.
>>
>> Hope that helps,
>>
>> Niklaus
>>
>> Niklaus Johner
>> Weill Cornell Medical College
>> Harel Weinstein Lab
>> Department of Physiology and Biophysics
>> 1300 York Avenue, Room D-501
>> New York, NY 10065
>>
>> On Mar 25, 2013, at 3:56 PM, Thomas C. Bishop wrote:
>>
>> This is for a molecular dynamics class I'm doing. The question has
>> come
>> up "What's pro/con of diff methods and which works best when & where."
>>
>> Aron gave an excellent start.
>> It would be great for experts to offer input and I"ll try to organize
>> into something useful.
>>
>> TOm
>>
>>
>>
>> On 03/25/2013 02:50 PM, JC Gumbart wrote:
>>
>> What are you trying to calculate specifically?
>>
>>
>>
>> On Mar 25, 2013, at 2:49 PM, Thomas C. Bishop wrote:
>>
>>
>> Does anyone happen to have a "cheat-sheet" with the pros and cons of
>> the diff free-energy methods or a review that provides this information.
>>
>>
>> Thanks in advance,
>>
>>
>> TOm
>>
>>
>>
>>
>> --
>>
>> *******************************
>>
>> Thomas C. Bishop
>>
>> Tel: 318-257-5209
>>
>> Fax: 318-257-3823
>>
>> www.latech.edu/~bishop
>>
>> ********************************
>>
>>
>>
>>
>>
>
>
> --
> Aron Broom M.Sc
> PhD Student
> Department of Chemistry
> University of Waterloo
>
>
>
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