q********g
发帖数: 10694 | 1 pH怎么在MD中实现？加H+么？
有没有文章推荐一下，不胜感激。 | G*****o
发帖数: 315 | 2 Interesting question. I do not know the answer though.
Adding H+ can be a simple solution. If you know the pH value, and also the
pKa of the amino acids, then you can selectively add H to some amino acids.
But if the pKa value of an amino acid is about equal to the pH, then I am
not sure whether you should add H or not.
This paper may be helpful.
Multiple pH Regime Molecular Dynamics Simulation for pK Calculations
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.p | q********g
发帖数: 10694 | 3 非常感谢啊～～
研究一下，在来问问。感觉自己还没入门不知道怎么问了。呵呵
.
【在 G*****o 的大作中提到】
: Interesting question. I do not know the answer though.
: Adding H+ can be a simple solution. If you know the pH value, and also the
: pKa of the amino acids, then you can selectively add H to some amino acids.
: But if the pKa value of an amino acid is about equal to the pH, then I am
: not sure whether you should add H or not.
: This paper may be helpful.
: Multiple pH Regime Molecular Dynamics Simulation for pK Calculations
: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.p
| q********g
发帖数: 10694 | 4 pH怎么在MD中实现？加H+么？
有没有文章推荐一下，不胜感激。 | G*****o
发帖数: 315 | 5 Interesting question. I do not know the answer though.
Adding H+ can be a simple solution. If you know the pH value, and also the
pKa of the amino acids, then you can selectively add H to some amino acids.
But if the pKa value of an amino acid is about equal to the pH, then I am
not sure whether you should add H or not.
This paper may be helpful.
Multiple pH Regime Molecular Dynamics Simulation for pK Calculations
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.p | q********g
发帖数: 10694 | 6 非常感谢啊～～
研究一下，在来问问。感觉自己还没入门不知道怎么问了。呵呵
.
【在 G*****o 的大作中提到】
: Interesting question. I do not know the answer though.
: Adding H+ can be a simple solution. If you know the pH value, and also the
: pKa of the amino acids, then you can selectively add H to some amino acids.
: But if the pKa value of an amino acid is about equal to the pH, then I am
: not sure whether you should add H or not.
: This paper may be helpful.
: Multiple pH Regime Molecular Dynamics Simulation for pK Calculations
: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.p
| q********g
发帖数: 10694 | 7 Constant pH Simulation
First, check your assumptions. The ideal situation would be to have a
constant-pH algorithm to perform the MD simulations. However, conventional
explicit-solvent MD algorithms cannot do that, since they're constant-H+
algorithms. Furthermore, if you use a MM force field, you will never get
protonation/deprotonation of sites in your solute: free H+ will just wander
around, while titrable sites are stuck with their initial protonation states
; if you want to overcome this you have to use a non-MM Hamiltonian which
explicitly allows for proton transfer. In any case, regardless of the
Hamiltonian used, the amount of H+ would never change.
If you want to do an explicit-solvent constant-pH simulation, the simplest
thing to do is to stick to conventional MD and just select the particular
amount of H+ that is "typical" for your system. You will need to use orders
of magnitude more water than are normally used in an MD simulation.
Basically, you can neglect free H+ concentration at most pH values (even at
pH=4) its concentration is orders of magnitude below that of other
counterions (eg, Na+, Cl-). Furthermore, as noted above, a pure MM
Hamiltonian will be unable to move protons between titrable sites (eg,
unlike EVB), so you actually need to choose the protonation state of each
titrable site in your molecule.
You can get a good guess at a starting configuration by performing a
standard pKa calculation with your starting structure; these are standard
procedures, mostly based on continuum electrostatics for computing
protonation free energies (eg, using MEAD, UHBD, DelPhi, APBS) and Monte
Carlo to perform sampling of protonation states (eg, using REDTI, PETIT).
Unfortunately, as the conformation of the solute changes along the MD
simulation, the protonation states may become inadequate, due to the strong
protonation-conformation coupling that exists in many cases. Several
solutions have been proposed, but most of them are more or less heuristic
attempts. The truly satisfactory solution would be to have a constant-pH MD
method, and some have been proposed in the last years. This has been
discussed on the GROMACS users mailing list. (Note that there is a serious
theoretical problem with a method by Phil Hunenberger.) Unfortunately,
constant-pH methods are recent and still under development and/or testing.
Hopefully, they will become standard methods in the near future. Maybe you
could one of these days just specify "pH = 7.0" in the GROMACS .mdp file and
see protonation states changing during the MD run! Until then, the best
solution is probably to one mentioned above: make an initial good guess with
a standard pKa calculation, and eventually check it later with snapshots
from the MD run.
There are constant pH simulation models, developed by Charlie Brooks and
others where you can simulate transfer of protons from one side chain to
another. They only work in implicit solvent so far (and in CHARMM at that).
There are several other constant-pH MD methods, some of them using explicit
solvent. Antonio Baptista's group has developed a constant-pH MD method
based on stochastic protonation changes (J. Chem. Phys. (2002) 117:4184).
Although the method uses a Poisson-Boltzmann method to periodically change
the protonation states, the MM/MD simulations are done with explicit solvent.
They have actually implementated this stochastic constant-pH MD method using
GROMACS (J. Phys. Chem. B (2006) 110:2927), basically following a stop-and-
go approach using bash and awk scripts to interface GROMACS with MEAD (a PB
solver by Don Bashford) and MCRP (a in-house program for Monte Carlo
sampling of protonation states). Unfortunately, the whole thing is still too
messy and hard-wired at some places, which makes it unsuitable to be
submitted as a contribution to GROMACS, at least for now.
Another explicit-solvent method, based only on MM/MD, was proposed by
Hunenberger (J. Chem. Phys. (2001) 114:9706), but its theoretical basis
seems to be wrong (J. Chem. Phys. (2002) 116:7766). As far as I know, all
other constant-pH MD methods proposed so far used indeed implicit solvent.
Stochastic approaches using implicit solvent were used by McCammon (J.
Comput. Chem. (2004) 25:2038) and by Antosiewicz (Phys. Rev. E (2002) 66:
051911), and Baptista's group has also proposed a fractional-charge approach
(Proteins (1997) 27:523) where implicit solvent was used for computational
speed; all these methods depend on some sort of simplified electrostatics-
oriented method (Poisson-Boltzmann, generalized Born, etc.) to perform the
protonation calculations. Implicit solvent was also used in a method
proposed by Brooks (Proteins (2004) 56:738), following a different but
theoretically vague approach to include protonation effects.
For discussion of water models that can dissociate, see this paper.
Notes
The above was pasted together from various emails on the GROMACS users
mailing list, but largely from some by Antonio Baptista. |
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