add hydrogens appropriate for pH

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add hydrogens appropriate for pH

Chris Swain
Hi,

I’ve been experimenting with the add hydrogens appropriate for pH and I get a couple of curious results

obabel -:"NC(=N)c1ccccc1" -osmi -p 7.4
N[C+](=N)c1ccccc1

Should this be [NH3+]C(=N)c1ccccc1

Similarly
obabel -:"NC(=N)Nc1ccccc1" -osmi -p 7.4
N[C+](=N)Nc1ccccc1

Should this be [NH3+]C(=N)Nc1ccccc1

obabel -:"Nc1ccccc1" -osmi -p 0.4
Nc1ccccc1

No matter how acid I set the pH aniline (pKa 4.6) is never protonated

How does the protonation work?

Cheers

Chris





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Re: add hydrogens appropriate for pH

Geoff Hutchison
No matter how acid I set the pH aniline (pKa 4.6) is never protonated

It's not a general model of pH-dependent protonation. It has a set of rules, particularly for amino acids.

For more accurate pKa determination, you'll probably want semiempirical quantum calculations or a more complete model. Several people have suggested interest and I've given them some pointers, but no contributions yet. (It's not trivial.)

-Geoff


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Re: add hydrogens appropriate for pH

Chris Swain
Thanks Geoff, I don't suppose the rules are in a user editable form?

Cheers

Chris

Sent from Chris's iPhone

On 18 Nov 2016, at 00:01, Geoffrey Hutchison <[hidden email]> wrote:

No matter how acid I set the pH aniline (pKa 4.6) is never protonated

It's not a general model of pH-dependent protonation. It has a set of rules, particularly for amino acids.

For more accurate pKa determination, you'll probably want semiempirical quantum calculations or a more complete model. Several people have suggested interest and I've given them some pointers, but no contributions yet. (It's not trivial.)

-Geoff


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Re: add hydrogens appropriate for pH

Giovanni Cincilla
The (de)protonation rules are stored as a list of transformation using SMARTS format in a file called phmodel.txtinside the data directory. Such file is editable but as Geoff suggested is not trivial to carefully enumerate all the potential transformations for many functional groups and substructures at different pH. As far as I know currently there is no open source software that do that properly, so any advance in this sense will be appreciated by the community.
Gio
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Re: add hydrogens appropriate for pH

Chris Swain
In reply to this post by Chris Swain
Hi,

Ok, I’ll have a look and see what I can contribute.

Cheers,

Chris

> The (de)protonation rules are stored as a list of transformation using SMARTS
> format in a file called /phmodel.txt/inside the /data/ directory. Such file
> is editable but as Geoff suggested is not trivial to carefully enumerate all
> the potential transformations for many functional groups and substructures
> at different pH. As far as I know currently there is no open source software
> that do that properly, so any advance in this sense will be appreciated by
> the community.
> Gio

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Re: add hydrogens appropriate for pH

Stefano Forli
Hi,
I gave it a shot and I think I got something working for the cases that Chris reported. In
the file phmodel.txt I've modified the line at the guanidine/amidine pattern as follows:

#guanidine or amidine
TRANSFORM *~[#6^2:1](~[#7:2])(~[#7:3]) >> *~[#6:1](=[#7+1:2])(-[#7:3]) 12.5 # NEW
#TRANSFORM [#6^2+0:1](~[N^2])(~[N^2])* >> [#6+:1](~N)(~N)* 12.5 # OLD

I believe there's a mistake is the definition of a net charge on the carbon, which is
unlikely to be there.
Also, the Daylight documentation doens't mention the "^" symbol in the SMARTS, but the
source of parsmart.cpp suggests that defines the hybridization (sp2, in the case above).
I've left it there and I've set an explicit double bond on one of the nitrogens.

If somebody has a more informed opinion on the matter, it's more than welcome, otherwise
I'll make a push request on GIT as it is.

Best,

S

On 11/18/2016 04:17 AM, Chris Swain wrote:

> Hi,
>
> Ok, I’ll have a look and see what I can contribute.
>
> Cheers,
>
> Chris
>
>> The (de)protonation rules are stored as a list of transformation using SMARTS
>> format in a file called /phmodel.txt/inside the /data/ directory. Such file
>> is editable but as Geoff suggested is not trivial to carefully enumerate all
>> the potential transformations for many functional groups and substructures
>> at different pH. As far as I know currently there is no open source software
>> that do that properly, so any advance in this sense will be appreciated by
>> the community.
>> Gio
>
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> OpenBabel-discuss mailing list
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>

--

  Stefano Forli, PhD

  Assistant Professor of ISCB
  Molecular Graphics Laboratory

  Dept. of Integrative Structural
  and Computational Biology, MB-112A
  The Scripps Research Institute
  10550  North Torrey Pines Road
  La Jolla,  CA 92037-1000,  USA.

     tel: +1 (858)784-2055
     fax: +1 (858)784-2860
     email: [hidden email]
     http://www.scripps.edu/~forli/

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Re: add hydrogens appropriate for pH

Chris Swain
In reply to this post by Chris Swain
Here are a few suggestions

Changed

#imidazole: note pKa=7.0
#if you uncomment this, also uncomment the seedcharge statement below
#TRANSFORM [nD2:1]1c[nH]cc1 >> [n+:1]1c[nH]cc1 7.0
To include N-alkylimidazoles
TRANSFORM [nD2:1]1c[nH,#6^3]cc1 >> [n+:1]1c[nH,#6^3]cc1 7.0


#guanidine or amidine

#TRANSFORM [#6^2+0:1](~[N^2:2])(~[N^2:3])* >> [#6+:1](~[N:2])(~[N:3])* 12.5
+ve charge on nitrogen not carbon. I +ve charge put on sp3 nitrogen for aesthetic reasons and to avoid potential issues with stereochemistry of C=N bond
TRANSFORM [#6^2+0:1](~[N^2:2])(~[N^2:3])* >> [#6:1](~[N:2])(~[N+:3])* 12.5


Added

#pyridine
TRANSFORM c1cc[nD2:1]cc1 >> c1cc[nH+:1]cc1 5.2


#Phenol
TRANSFORM c1ccccc1[OD1-0:1] >> c1ccccc1[O-:1] 10


As Stefano mentioned it is likely that the guanidine or amidine was an error, if you look at the seed charges the for guanidine or amidine the +ve is on the nitrogens.

I could add a few more but I thought it would be worth getting some feedback first.

Cheers

Chris
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Re: add hydrogens appropriate for pH

Geoff Hutchison
> I could add a few more but I thought it would be worth getting some feedback first.

Oh, I think there's some general interest in improved patterns. :-)

-Geoff
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Re: add hydrogens appropriate for pH

Stefano Forli
If you guys are OK with it, I could collect them and put them together in a single pull to
the code (with due credits, of course).

On 11/20/2016 03:34 PM, Geoffrey Hutchison wrote:

>> I could add a few more but I thought it would be worth getting some feedback first.
>
> Oh, I think there's some general interest in improved patterns. :-)
>
> -Geoff
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--

  Stefano Forli, PhD

  Assistant Professor of ISCB
  Molecular Graphics Laboratory

  Dept. of Integrative Structural
  and Computational Biology, MB-112A
  The Scripps Research Institute
  10550  North Torrey Pines Road
  La Jolla,  CA 92037-1000,  USA.

     tel: +1 (858)784-2055
     fax: +1 (858)784-2860
     email: [hidden email]
     http://www.scripps.edu/~forli/

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