Antw: Re: Re: Antw: Re: Re: [gmx-users] constant PH simulations

baptista baptista at
Thu Sep 8 06:52:18 CEST 2011

 Dear Emanuel,

 Here are a few comments that may help your way through the literature 
 already pointed out by others.

 Most of your questions concern temporal/kinetic aspects (interchange 
 times, etc) and the answer to them is quite simple: constant-pH MD 
 methods are intended to produce a collection of microstates that is 
 representative of equilibrium, regardless of their temporal relation -- 
 that is, they are *sampling* methods. The rationale is that you ignore 
 the real physical process responsible for the (de)protonation changes 
 and, instead, devise a mathematical strategy to produce a good sample of 
 their distribution.

 If you think about it, the same holds for all other methods to run 
 simulations in non-microcanonical ensembles. For example, when you use a 
 Nose-Hoover bath for constant temperature, you do not try to explicitly 
 account for the transfer of momentum from external environment through 
 the vibrational modes of the material of the container walls -- rather, 
 you simulate a totally unphysical "extended" system in the 
 microcanonical ensemble, which produces a distribution of microstates 
 whose projection on the subspace of your real system happens to be the 
 canonical distribution of the latter. Luckily, the transfer of momentum 
 is so fast that, as long as the MD moves preserve some kinetic 
 contiguity of the microstates, it is easy to get realistic temporal 
 properties by tuning the values of the bath coupling parameters (or 
 piston masses, etc). Unfortunately, the same cannot be done for proton 
 exchanges in constant-pH MD, for two main reasons. First, exchanges with 
 the solvent depend on slow bimolecular collisions (on the microsecond or 
 slower timescale) and thus cannot be sampled in a temporally realistic 
 way with current computer power. Second, the times of intramolecular 
 exchanges depend on the groups involved and would require computing the 
 corresponding free energy barriers. Therefore, even in the case of 
 "discrete" constant-pH MD methods (where sites are empty or occupied 
 with "full" protons), you cannot easily adjust a parameter to get 
 realistic exchange rates. In the case of "continuum" constant-pH MD 
 methods (where sites are occupied by "fractional" protons), asking for 
 realistic exchange rates is bit like asking for temporal realism in free 
 energy calculations using thermodynamic integration or perturbation 
 methods -- the very question becomes meaningless. In short, the studies 
 published so far show that constant-pH MD seems to work pretty well in 
 accounting for (de)protonation-induced structural reorganization (there 
 are actually plenty of comparisons with experimental data; check the 
 literature), but it is obviously not the way to go if you want to 
 investigate rates and energy barriers (in which case you can use 
 MM-based free energy methods or, instead, quantum or semiclassical 
 methods that explicitly model proton association/dissociation).

 Once you understand that time is not really there in the constant-pH MD 
 "simulations", the usual absence of H+ in the box should become clear -- 
 you just do what you would normally do in a traditional 
 constant-protonation run. So, in most cases you would not add any 
 H+/H3O+/OH- ions, although you may want to at extreme pH values 
 (assuming you have reasonable MM models for that, which is arguable). 
 That's why I stated in one of the papers that you should probably read: 
 "As usual in binding formalisms [refs], we restrict the location of 
 transient protons to the protonatable sites; non-binding protons can be 
 considered as part of the solvent if necessary." [J. Chem. Phys. 
 107:4184] Essentially, this follows from the statistical thermodynamic 
 fact that sampling and Hamiltonian are independent things, so you should 
 use the same type of model in the constant-protonation and constant-pH 
 cases, because the former is a conditional case of the latter.

 I hope this helps your reading of the literature. Some statistical 
 thermodynamics background is also the best way to clarify the more 
 conceptual issues. Note also that there are considerable differences 
 between some of the constant-pH MD methods currently in use (Gerrit was 
 mostly commenting on one particular type of "continuous" method).


 Antonio M. Baptista
 Instituto de Tecnologia Quimica e Biologica, Universidade Nova de 
 Av. da Republica - EAN, 2780-157 Oeiras, Portugal
 phone: +351-214469619         email: baptista at
 fax:   +351-214411277         WWW:

 On Wed, 07 Sep 2011 13:41:33 +0200, Emanuel Peter wrote:
> SMA.
>>>> João Henriques 07.09.11 13.09 Uhr >>>
> Why don't you read the papers associated with the link everyone keeps
> sending you!!!
> Stop it with the autistic behavior.
> Here is the main paper regarding the CpH-MD method I'm currently
> using:
> Here's a tip: searching google scholar a little before emailing
> everyone in the list should prove useful.
> Cheers,
> On Wed, Sep 7, 2011 at 11:01 AM, Emanuel Peter
>  wrote:
>> At first I would like to say that I deeply apologize for
>> the cave-like things I have said. I again say, that this
>> was not the field I am deeply involved.
>> From Gerrit I got a banana.
>> For this guy, I am a cave-man.
>> Thanks, for being such ready for open discussion.
>> I did not tell that I do not want to be wrong.
>> Questions, which are included in my doubts:
>> Generalized forces and averages for H+ interchange ?
>> Comparison with titration experiments ?
>> Is there any experimental evidence for the rates of
>> interchange ?
>> Are simulation-times or the periods of interchange at
>> any time realistic?
>> Are equilibria sampled well, with such interchanges,
>> or are there jumps in free energy by this interchange ?
>> Why is there no free H+ ?
>> Thanks for your kind and very constructive criticisms.
>> I would appreciate, if this so-called discussion will
>> find an end.
>> I am deeply depressed about such comments and
>> I will not take part in any users-discussion in the future.
>> It makes no sense, because talking like this expresses
>> the way on how science is done today. Repelling that
>> person, who does not walk the common way.
>> And:
>> Maybe I have lived in a cave, but someone like you, who answers in
>> such a way, IS A CAVEMAN !
>>>>> João Henriques 07.09.11 11.30 Uhr >>>
>> There is no problem in being wrong. The problem is that he wants to
> be
>> wrong. At least 4 different researchers gave constructive input and
>> this subject keeps hitting the same key. I've always been told that
>> worse than not knowing, is not wanting to know.
>> Still, I apologize for my outburst.
>> Best regards,
>> On Wed, Sep 7, 2011 at 1:54 AM, Mark Abraham
>> wrote:
>>> On 7/09/2011 3:53 AM, João Henriques wrote:
>>>> I guess someone has been living in a cave for the past decade or
> so...
>>> Please keep contributions to the mailing list constructive :-)
> Everyone's
>>> been wrong before!
>>> Mark
>>> --
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>> --
>> João Henriques
>> --
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>> Please search the archive at
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>> --
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