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).
Best,
Antonio
--
Antonio M. Baptista
Instituto de Tecnologia Quimica e Biologica, Universidade Nova de
Lisboa
Av. da Republica - EAN, 2780-157 Oeiras, Portugal
phone: +351-214469619 email: bapti...@itqb.unl.pt
fax: +351-214411277 WWW: http://www.itqb.unl.pt/~baptista
--------------------------------------------------------------------------
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.
http://www.gromacs.org/Documentation/How-tos/Constant_pH_Simulation
Here is the main paper regarding the CpH-MD method I'm currently
using:
http://jcp.aip.org/resource/1/jcpsa6/v117/i9/p4184_s1
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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