Re: About the scope of show_replicas.vmd

From: Francesco Pietra (
Date: Fri Sep 20 2013 - 02:33:19 CDT

Hi Niklaus:

What I am trying to do is defining the conformation of starting and ending
parts of a homotrimer. These portions, 34aa and 12aa for each subunit in
our hands do not diffract adequately under x-ray at low temp. So, I guess
that the energy barriers are low. This is why my hope to get that type of
T-remd convergence I alluded to. Once modeled, those parts should be
replaced in the original (by superimposing a rmsd-colvars restrained small
helical portion).

Computer time does matter for me indeed, as I am trying to accomplish the
investigation under a fixed budget. I first tried the 34aa in TIP3 water
but the request of hardware, in terms of physical nodes, was too high to
fix "Stray PME grid charges detected" that was raised. Therefore, I changed
to implicit GB, following other-people idea that most of the resources for
explicit waster T-remd are wasted with swapping water interactions. GB runs
fast, however I don't know if is as good as with latest adjustment of
parameters for amber (C. Simmerling 2013).

Clearly, I need a test of convergence that is not that provided by
"show_replicas.vmd". I wonder whether the collection of replicas obtained
with show_replicas.vmd could in place be elaborated, such as for measuring
RMSD for the various replicas against the initial unfolded situation. Just
to have a measure of how much the various replicas differ from one another.
As I am using 32 replicas (0.7 exchange ratio), the matter is rather
tricky. With 16 replicas the exchange ratio is still very good (0.4) but
the computer time saved is minimal (and I pay the same as for 32 replicas).
I hope that convergence is faster with 32 replicas. As a biochemist, I
never engaged myself in extensive coding, while it would be probably not
too difficult to adapt show_replicas.vmd to the task. I have also thought
to move to namd_2.10, where remd is built in, so that it should be faster.


On Thu, Sep 19, 2013 at 7:30 PM, Niklaus Johner <>wrote:

> Yes each replica samples from the same "extended" phase-space so that if
> you wait long enough, each replica will have visited each conformational
> state often enough to have a converged statistic of that state's occupation
> at the different temperatures and therefore you'll be able to say that, as
> Jason points out, your replicas have converged.
> So fundamentally I agree with you that obtaining this kind of convergence
> would be ideal (if not proof of convergence). I just think it's not
> realistic with our current simulation capabilities, except for very small
> systems with a reasonably small number of degrees of freedom, like the
> alanine-dipeptide (that's why all the papers introducing new sampling
> methods only look at the dipeptide and the TRP-cage :-)). So if you get
> convergence of the probabilities of occupancy of the few most sampled
> states, that would already be an achievement and is, in my opinion, enough
> to give you some confidence in the conformations you predict.
> How big is your peptide?
> Obviously looking at different measures of convergence will increase your
> confidence in your sampling. You could look at frequency of certain
> structural elements, convergence of contact maps etc. Split the simulation
> in pieces and compare, compare different replicas...
> A good way to speed up convergence is to start each replica from a
> different configuration. Again, I know it shouldn't matter if you wait long
> enough, but again, I think it's usually not an option to wait that long.
> Best,
> N.
> 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 Sep 19, 2013, at 11:53 AM, Francesco Pietra wrote:
> Absolutely no. Each individual replica samples from the same pool.
> Therefore, if you do not get the same from each individual replica, this
> means no convergence. It might be difficult to get convergence but, if not
> obtained, it would be non scientific to go to "sortreplicas" to compute
> properties at the temperature of your interest.
> This is the way I understand T-remd. But I am prone to reeducate myself in
> the light of compelling reasoning. This was not the case so far.
> cheers
> francesco pietra
> On Thu, Sep 19, 2013 at 4:48 PM, Niklaus Johner <>wrote:
>> What do you mean by "giving the same answer"? Are you hoping that all
>> your replicas will converge to a unique structure? The whole point of
>> T-remd is that the replicas switch from one temperature to another, to
>> avoid getting stuck in a particular minimum. I think the expectation is
>> that even if you could run long enough to have "convergence", meaning that
>> you have the correct populations for all the important states, which is
>> more than you can hope for, this would be a global convergence of the
>> T-remd and not of the individual replicas. Different replicas might explore
>> the phase-space around different local minima, but should populate the
>> lower temperatures in the simulation according to the relative energies of
>> these minima. So I think what you want to test is if the population of
>> states in the lowest temperatures is stable. So I would do clustering on
>> different parts of the trajectory and compare the clusters of highest
>> occupancy, or something like this.
>> Be aware that you can never really know if a simulation is converged. How
>> could you know if you've seen all the important conformations? Maybe the
>> most important conformation, with lowest free-energy can be reached from
>> your starting configuration only by crossing a very high energy barrier, so
>> that you will never see it, and all the measures you can come up with could
>> tell you that it's converged. It's probably one of the biggest issues with
>> MD.
>> Good luck,
>> N.
>> 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 Sep 19, 2013, at 2:48 AM, Francesco Pietra wrote:
>> Hello:
>> I posed the same question to the vmd forum but probably is to the namd
>> forum pertinent for the question.
>> Thus, I carried out a short T-remd on alanin with 8 replicas, as provided
>> by namd_2.9. I used the final namd-provided folded pdb for comparison. The
>> script show_replicas.vmd with these replicas warned "not converged".
>> With my peptide, 32 replicas, after 370,000 steps still far from
>> convergence, I used, for the vmd comparison, the starting unfolded.pdb also
>> as a fake folded.pdb. In this case, show_replicas.vmd did not raise any
>> warning. Looking also at the code, it seems to me that show_replicas.vmd
>> assumes, as a criterion of convergence, the comparison of the various
>> replicas with the pdb file that you give as folded peptide in the
>> fold.peptide.conf file. That works if your T-remd is just devised to check
>> if you are able to reproduce an experimentally defined situation.
>> Suppose instead that your T-remd is devised to search for the best
>> conformation, or cluster of conformations, for an experimentally undefined
>> peptide. I can imagine many situations where the experimental approach is
>> problematic. Then you need a real criterion of convergence of yor T-remd,
>> before starting to examine the (sorted) same-T replicas. Obviously, a
>> reliable criterion of convergence is that what you get must be the same
>> from each replica, for example that the average structure is the same from
>> all replicas.
>> Therefore, I got the impression that the warning "not converged" raised
>> by show_replicas.vmd is misleading. Is any script available to check when
>> any replica gives the same answer.
>> Thanks for advice, even if showing that I am wrong.
>> francesco pietra

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