Re: [AMBER] N- and C- terminals constant PH simulation

From: Hadeer ELHabashy <>
Date: Wed, 11 Nov 2015 11:16:56 +0200

Dear Sir

Wish you are fine !

Is it possible to run the terminals at different but fixed protonation
states using AMBER force field without capping with AMBER/sander or
AMBER/pmemd ?!!
If not, is it possible to run the terminals at different but fixed
protonation states using GROMOS force field with AMBER/sander or AMBER/pmemd

On Tue, Oct 27, 2015 at 5:34 PM, Jason Swails <>

> On Tue, Oct 27, 2015 at 9:32 AM, Hadeer ELHabashy <
>> wrote:
> > Dear Sir
> > wish you are fine !
> > It is mentioned in AMBER15 user manual that
> > " There is currently no support for titrating N or C terminal residues."
> > And I don't not understand why?
> > If AMBER can do it for titratable amino acid side chains, why not for the
> > C- and N terminal ? What is the challenge in this ?!
> >
> It requires a *lot* of work, there are significant technical challenges
> that would need to be dealt with (relating to changing backbone charges
> introducing sequence dependent reference energies), and the experimental
> data for amino acid terminus pKa values are less abundant and reliable.
> For me (I spent my graduate school years working on the constant pH MD
> methodology in Amber), supporting termini was too much work for far too
> little benefit to make it worth my while.
> Add in the fact that the terminal protonation states are *far* less likely
> to be important for protein structure, dynamics, or function and it is a
> recipe for not being supported.
> Is there any other method that can be used for titrating the C- and N
> > terminals and prepare them for AMBER constant PH simulation ?!!
> >
> ​I'm not sure. Some of the servers (maybe H++ or PROPKA) might give you
> estimates. And CHARMM might work as well, but I've never tried this
> before.​
> All the best,
> Jason
> P.S., to give a glimpse into the amount of work that would be required --
> the current CpHMD implementation required creating 2 new residues -- AS4
> and GL4 -- and required only a single RESP charge fit (deprotonated
> tyrosine, which wasn't already present in Amber). Supporting termini would
> require constructing new C-terminal residues for *every* amino acid --
> about 20 of them -- as well as fitting charges for 40 different residues
> that do not already have templates (the neutral termini). Then the
> sequence dependence of the reference energies (caused by the 1-4
> interactions which are scaled) would probably require separate reference
> energies for each *pair* of C-terminal or N-terminal residues, which could
> bring the number of required reference energies to 400... per terminus (by
> comparison, we have ~10 with the titratable residues supported now). It
> may not be quite this bad -- there are only 3 different sets of backbone
> charges, so that 400 may be closer to 60, but there's no way of knowing
> without trying it.
> Then you have the complication of how do you treat a C-terminal aspartate
> or glutamate? That's a very complex residue to assign reference energies
> for as well, and I don't know that the experimental pKas for the two sites
> have been fleshed-out.
> And to keep this all in perspective, the termini are really not that
> important in the vast majority of cases.​
> --
> Jason M. Swails
> BioMaPS,
> Rutgers University
> Postdoctoral Researcher
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Received on Wed Nov 11 2015 - 01:30:04 PST
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