Re: [AMBER] Explicit Solvent Constant pH MD

From: Rahul Ramesh <>
Date: Thu, 9 Jul 2015 12:42:17 -0400

Thank you Jason for the wonderful inputs. I'm currently working on the
aspartic acid residue and I would like to know the charge methods you used
to derive those charges and also which force field is used? I calculated my
partial charges using acpype which uses bcc and amber 99SB forcefield?

Rahul Ramesh
Masters Student
Department of Chemical Engineering
University of Michigan Ann Arbor
(+1 734-680-4453)

On Tue, Jun 30, 2015 at 11:11 PM, Jason Swails <>

> On Tue, Jun 30, 2015 at 4:53 PM, Rahul Ramesh <> wrote:
> > Hello
> > I am using AMBER's constant pH MD to study the effect of drug on a
> polymer
> > having carboxylic acid side chain. To start off with , I am currently
> > trying to simulate a monomer which has a cellulose ring with a COOH group
> > attached. The simulation is performed using amber 14 explicit solvent
> > constant pH MD following Jason Swails tutorial. Since my system does not
> > resemble any protein residue , I modified the * *code to
> > incorporate my monomer. The force field used is AMBER 99 SB. The cpin
> file
> > generated looks fine. The reference energy for the protonated
> deprotonated
> > transition was obtained by performing a Thermodynamic Integration (TI) .
> As
> > a test case , I set the solvph equal to the pKa of the carboxylate side
> > group. While performing MD , there are no transitions between the
> > protonated and deprotonated states of the monomer. The system is always
> in
> > the protonated state for 2 ns.
> > I have four questions regarding this ,
> >
> > 1) As of now , I have only one titratable residue ( monomer has 35 atoms
> > totally ) which is initially in its protonated state , I would like to
> know
> > if ions need to be added in the system while doing explicit solvent
> > constant pH MD. If so how many ?
> >
> ​I would add a "typical" amount. The ions don't play any direct role in
> the protonation state change evaluations -- only through its influence of
> the system dynamics. So the exact number in this case is not terribly
> important.
> ​
> > 2) Is there any reason why transitions between protonated and
> deprotonated
> > wouldn't happen? Is the amber 14 constant pH MD tuned only to titrate
> > proteins?
> >
> ​No, the code is completely general and will work for literally any
> titratable residue definition that is properly defined in If
> you are not getting transitions for the model compound when titrating at pH
> = pKa, then your reference energy is wrong. It's really as simple as that
> (which is nice). But there are so many ways that you can get the reference
> energy wrong that it's impossible to guess exactly which one you happened
> to do here.
> ​​
> > 3) I would like to know the units of the reference energy which are given
> > ​​
> > in the python code * *
> >
> ​kcal/mol
> 4) Suppose I want to perform this simulation in implicit solvent just in
> > case explicit solvent doesn't work, how can I obtain the partial charge
> > information for my polymer accounting for implicit solvents
> >
> ​The residue definition for implicit and explicit solvent are exactly the
> same. And the reference energies are derived similarly and are often very
> similar. Both use TI in GB as a starting point (which gets you very
> close), and then uses a titration to compute the pKa of the model
> compound. The shift between the actual computed pKa and the target pKa you
> get from experiment can be used to tweak the reference energy to its
> correct value.
> The fact that TI and the procedure described above agree so well is
> necessary, but not necessarily sufficient to show that the method is
> implemented correctly. There are some disparities between the TI and
> reference energies in some instances; for carboxylates there is an entropic
> factor that will make the TI energy differ from the reference energy (there
> are 2 sets of 2 degenerate proton positions on each oxygen for the
> protonated state and only a single deprotonated state). But for histidine,
> the TI and reference energies are spot-on.
> One thing you need to take care with is that your TI has to be computed
> with *exactly* the same settings (same solvent radii, same charge sets,
> same residue with the same dummy atoms in the same places, same GB model,
> ... etc.). Any difference between these two will make your reference
> energy wrong by a potentially very large amount. This is actually why the
> implicit and explicit reference energies for AS4 and GL4 are so different
> -- the solvent radii in the explicit definitions for the carboxylate
> oxygens are smaller than in implicit solvent, so the reference energy is
> therefore very different.
> ​In my opinion, what you are trying to do is a challenging, long-term
> problem. I spent the better part of 1 to 2 years studying the method, the
> code, and experimenting with different ideas before I understood the model
> well enough to extend it the way I did to explicit solvent and to compute
> reference energies and define titratable residues reliably and efficiently.
> (Actually, the ParmEd program was born from the collection of the tools I
> wrote specifically to try out my ideas for constant pH MD).
> If you are prepared to invest the necessary time to learn how to do this,
> the best advice that I can give is step back from your current residue you
> are trying to define. Instead, start with with something you *already*
> know the answer for. Make a copy of (and the cpinutils
> package). Delete the AS4 or GL4 definition in there, and try to create the
> definition yourself. Once you have a recipe that you can use to reproduce
> the same AS4 or GL4 definition as mine, then take that recipe and apply it
> to your residue. Even better if you can take that recipe and turn it into
> a generalized script that people can use for their *own* titratable
> residues!
> The concept of defining a titratable residue is itself simple and
> straightforward. But this is an excellent example of the phrase "the
> devil's in the details". There are a *lot* of details that are omitted
> when people talk about defining references and reference energies (simply
> because it would be way too verbose to include them all).
> I hope this helped,
> Jason
> P.S., you are welcome to ask questions to the list as problems arise, but I
> doubt there are very many people that will know the details well enough to
> provide much detailed help. I will try and assist as time permits, but
> this will likely require a significant time investment on your part.
> --
> Jason M. Swails
> BioMaPS,
> Rutgers University
> Postdoctoral Researcher
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Received on Thu Jul 09 2015 - 10:00:03 PDT
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