Re: [AMBER] [Sender Not Verified] Regarding Determination of HIS Residue States

From: Steinbrecher, Thomas via AMBER <>
Date: Mon, 12 Jun 2023 11:51:42 +0200

Hi Xiaochun,

I'd be curious if others have more informative answers here, but my guess
is that you are specifying an important problem in modelling of proteins
that remains mostly unsolved. There is no 'correct' state. The three states
of Histidine (plus flips if you want to count the conformations extra) are
sufficiently similar in free energy that each of them can be relevant in
any system, based on the surroundings. Since molecular mechanics based
modelling has to pick a state for each His, you are left with making an
informed guess and that is what the tools you mention try to do, with
reasonable but not perfect levels of success. One way out of the problem
would be simulations which allow the Histidines to change state like
constant pH MD. Another could be to use QM or FEP type calculations to
decide in each specific case what the most important state of a His is. Or
you have to bite the bullet and simulate each possible state (including the
combinatorial explosion problem if you have several His in your pocket) and
try to combine the results.

Kind Regards,


On Mon, Jun 12, 2023 at 10:15 AM zhangxiaochun via AMBER <>

> Dear Amber community,
> I am writing this email to discuss the issue of determining the states of
> HIS residues in simulations. Recently, I have been using several tools such
> as H++, PDB2PQR, and Schrodinger to predict the states of HIS residues in
> the same protein. However, the results provided by these tools are often
> inconsistent, which has left me confused. I would greatly appreciate your
> advice and input in determining which tool to use or how to establish the
> correct state.
> While using tools like H++, PDB2PQR, and Schrodinger for prediction, I
> have encountered the following challenges:
> Inconsistent results: The predicted HIS states differ among the different
> tools. For example, some tools predict the protonated form, while others
> suggest the deprotonated form. This discrepancy has made it difficult for
> me to choose the correct state.
> Credibility concerns: Each tool has its own algorithm and assumptions,
> making it challenging to determine which prediction is the most reliable
> and accurate. I need further guidance to determine which result to trust.
> Thank you very much for your assistance!
> Warm regards,
> Xiaochun Zhang
> _______________________________________________
> AMBER mailing list

*Dr. Thomas Steinbrecher*
Principal Scientist CADD
Roche Pharma Research and Early Development
Roche Innovation Center Basel
F. Hoffmann-La Roche Ltd
Bldg. 092/3.92
Grenzacherstrasse 124
4070 Basel
Phone +41 61 682 1319
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Received on Mon Jun 12 2023 - 03:00:02 PDT
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