From: Jason Swails <>
Date: Tue, 24 Mar 2015 21:36:02 -0400

On Tue, Mar 24, 2015 at 1:37 PM, Arjun Sharma <>

> Dear Amber users,
> I’m wondering if it is possible to run CpHMD-pHREX in AMBER 14 for the
> organic polymer with -COOH functional group. I see that leaprc.constph is
> mostly set up for amino acids and since I am dealing with non-standard
> residues , how do I go about it ?

​This is a more challenging problem than it may at first appear. Basically
what you need to do is define the charge vectors for each of the
protonation states that you want to allow your new titratable residue to
have access to. Then, you need to compute the reference energy, which is
the energy at which some model compound titrates to the *correct*
experimental pKa.

So you need a representative compound for which you know an experimental
pKa, you need to estimate its reference energy (thermodynamic integration
will often get you either the correct reference energy or it will get you
very close). Then you need to run a titration of your model compound to
make sure that the computed pKa matches the target pKa. If it doesn't, you
need to adjust your reference energy so that it does.

This is a very basic overview of what needs to be done. Going into the
specifics, giving you a step-by-step workflow to implement it yourself
would take me too long to put it into an email, so you will need to do a
lot of the legwork yourself. I suggest starting with Mongan's original
paper, read a couple of mine and Adrian's, read the Amber manual chapter on
constant pH MD (which briefly describes the steps necessary to create your
own titratable residue), read the code if such things help you understand
stuff, and most importantly, experiment and try things out.

Note that I spent the 5 years of my graduate career on this method. As a
novice to Amber and the field in general when I started, it took me the
better part of a year to understand the finer details of the method, and
closer to 2 until I got to the point where I was able to implement the
explicit solvent model and develop a rigorous workflow to parametrize new
residues (or reparametrize existing residues for new solvent models). I
had some scripts that would automate parts of the workflow, but for the
most part I did it by hand to make sure at each step that everything was
correct. Was I not new to the field at the start (but just new to CpHMD),
it would not have taken as long; but I don't know how long it would have
taken me in that case.

I'm not trying to discourage you from pursuing this (quite the opposite!),
but I want to stress that this task is *not* simple and could require a
substantial time investment to implement. (And if you do, I would
encourage you to contribute the parameters for the new residue you
parametrized back to Amber so others can benefit from---and cite---your


Any help is appreciated.
> Thanks,
> Ashar
> _______________________________________________
> AMBER mailing list

Jason M. Swails
Rutgers University
Postdoctoral Researcher
AMBER mailing list
Received on Tue Mar 24 2015 - 19:00:03 PDT
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