[Chimera-users] Charge assignment to a ligand

Tue Apr 14 08:20:04 PDT 2020

Hi Prabuddha,
Chimera attempts to make a reasonable protonation state at approximately neutral pH  (pH 7).   In general, aliphatic amine pKa's are higher than aromatic amine, so they would get assigned an atom type in Chimera that will result in a positive net charge after hydrogen addition.  However, there is no detailed calculation of pKa of each group, only an approximate attempt to identify atom types before adding the hydrogens.  This is explained in the link I sent earlier:
>> How AddH in Chimera works is explained here:
>> <http://www.rbvi.ucsf.edu/chimera/docs/ContributedSoftware/addh/addh.html>

You can control protonation exactly by changing heavy (nonhydrogen) atom types in Chimera before adding hydrogens, but this is more work for you.  For list of atom types and an example of how to change them, see this previous post:
<http://www.cgl.ucsf.edu/pipermail/chimera-users/2017-June/013550.html>

Or, you could try finding some other program (not Chimera) that would do a more detailed pKa and protonation state prediction. For example, PROPKA:
<https://pypi.org/project/PROPKA/>

 I hope this helps,
Elaine
-----
Elaine C. Meng, Ph.D.                       
UCSF Chimera(X) team
Department of Pharmaceutical Chemistry
University of California, San Francisco

> On Apr 13, 2020, at 11:17 PM, Prabuddha Bhattacharya <b.prabuddha3 at gmail.com> wrote:
> 
> Dear Sir,
> 
> Thank you for your clarification.
> 
> Just a follow up question: What makes the 'add hydrogen' option protonate an aliphatic amine and skip when it comes to an aromatic proton? Since in both the cases, N is valency wise saturated (trivalent), so what prompts/ guides this differential protonation? Is it pH guided?
> 
> For your kind reference, I am sending image (as attached tiff file) of such a substrate. 
> 
> With reference to the image, N1 (in red) is a part of aromatic framework, N2 (in blue) is an aliphatic amine moiety. Both are trivalent (and hence valency wise saturated). Upon activating the 'add hydrogen' option, it is N2 (the aliphatic one) that gets protonated and hence goes to the hypervalent state (as it now becomes tetravalent) but N1 remains unprotonated.
> 
> My question is that upon what basis is this differential protonation done by chimera? Is is guided by their (N1 and N2's) relative pKb (basic strengths) values under a particular pH?
> 
> I will be grateful if you can explain me this issue.
> 
> Thanking you in advance,
> 
> Best Regards,
> 
> Dr. Prabuddha Bhattacharya
> Dept. Of Chemistry
> Adamas University
> Kolkata-700126
> India
> 
> 
> 
> 
> On Tue, Apr 14, 2020 at 1:34 AM Eric Pettersen <pett at cgl.ucsf.edu> wrote:
> If you want Chimera to use the protonation state of your structures “as is” and not add any hydrogens of its own, then you need to uncheck the “add hydrogens” check box of Dock Prep (which is also a substep of minimization).  Adding hydrogens will not remove any hydrogens, but will usually add protons to e.g. aliphatic amines, as per your experience.  This is because some PDB structures are only partially protonated, and therefore Chimera does not assume that the presence of pre-existing hydrogens means that adding hydrogens should be skipped.
> 
> --Eric
> 
> 	Eric Pettersen
> 	UCSF Computer Graphics Lab
> 
> 
>> On Apr 13, 2020, at 12:21 PM, Elaine Meng <meng at cgl.ucsf.edu> wrote:
>> 
>> Dear Dr. Prabuddha Bhattacharya, 
>> You didn't say if you used Chimera to add hydrogens or whether the structures already had hydrogens when they were opened.
>> 
>> If you used Chimera to add hydrogens, it tries to generate states reasonable at neutral pH.  For example, it will not add hydrogens to aspartic acid and glutamic acid side chains of a protein. (If Chimera is adding the -COOH hydrogen, it may be that the atom-type guessing is wrong because the -CO bond lengths are not consistent with a carboxylate group.)
>> 
>> How AddH in Chimera works is explained here:
>> <http://www.rbvi.ucsf.edu/chimera/docs/ContributedSoftware/addh/addh.html>
>> 
>> However, if your molecules already had the hydrogens on them when they were opened (or fetched from PubChem or by SMILES string), Chimera doesn't delete the hydrogens.... it assumes that is what you want.  You should manually delete the hydrogens you don't want.  Or if it's easier, you could try deleting all hydrogens (e.g. command: delete H) and then adding them back with Chimera, but it may not work the way you want if the bond lengths are not consistent with the negatively charged -COO group.
>> 
>> The force field does not do anything to change protonation states, it just tries to work with what it is given: whatever hydrogens were read in with the structure, or were added in Chimera before charge calculation.
>> 
>> I hope this helps,
>> Elaine
>> -----
>> Elaine C. Meng, Ph.D.                       
>> UCSF Chimera(X) team
>> Department of Pharmaceutical Chemistry
>> University of California, San Francisco
>> 
>>> On Apr 13, 2020, at 11:51 AM, Prabuddha Bhattacharya <b.prabuddha3 at gmail.com> wrote:
>>> 
>>> Dear Sir,
>>> 
>>> I had a query regarding charge assignment to any ligand in chimera. 
>>> 
>>> While minimizing the energy of a particular ligand (Tools --> Structure Editing --> Minimize Structure) and also during Dock Prep, I found that for most of the aliphatic and alicyclic amines, they are getting protonated with a residual positive charge; while the aromatic amines remain unprotonated (and hence no residual charge). I understand that this is because of their differential pKb values (basic strengths). 
>>> 
>>> On the other side, deprotonation never occurs with the carboxylic acid (-COOH) group.
>>> 
>>> Does the Chimera (force fields) control this issue of protonation and deprotonation considering the physiological pH ?
>>> 
>>> I will be extremely grateful if some one may kindly clarify my doubts.
>>> 
>>> Thanking you in advance,
>>> 
>>> With Best Regards,
>>> 
>>> Dr. Prabuddha Bhattacharya 
>>> Dept. Of Chemistry
>>> Adamas University
>>> Kolkata 700126
>>> India
>>> 
>>> _______________________________________________
>>> Chimera-users mailing list: Chimera-users at cgl.ucsf.edu
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>> 
>> 
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