From: Niklaus Johner (niki.johner_at_gmail.com)
Date: Thu Sep 19 2013 - 12:30:05 CDT
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.
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.
> francesco pietra
> On Thu, Sep 19, 2013 at 4:48 PM, Niklaus Johner <niki.johner_at_gmail.com> 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,
> 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:
>> 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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