[Chimera-users] Charge assignment to a ligand

[Prabuddha Bhattacharya]

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
>
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