Addh protonates metal-coordinated cysteines

[Tristan Croll]

Sorry to keep picking on AddH - it's a really useful tool that's making my life a whole lot easier.

Example: 3eyl. Cysteines B300,303,327 are coordinated around a zinc ion (with pseudobonds correctly added by ChimeraX). addh hbond true currently adds hydrogens to the sulfur atoms.

[Eric Pettersen]

Hi Tristan,
	Lukas Pravda raised the same issue, and here’s the relevant section of the discussion that Elaine and I had with him:

	The protonation state of moieties coordinating a metal ion is a complex issue, which does not lend itself well to automated schemes.  The two options are: 1) to treat the coordination bond like a covalent bond, or 2) not treat it as a covalent bond but ensure the lone pairs are oriented along the coordination bond.  We opted for the latter since it typically leads to at least reasonable chemical systems, whereas the former, though possibly/probably correct in many situations, leads to clearly wrong behavior in at least a significant subset of cases.  For instance, suppose that instead of water, the iron-coordinating entity was molecular oxygen (O2) or carbon monoxide (CO-)?  Unless you had special-case handling, oxygen would be treated like hydrogen peroxide, and carbon monoxide like methanol, and you would clearly get the wrong overall protonation.
	For the particular case of heme coordination, the following papers suggest that neutral thiol (SH) sometimes ligates the heme iron:

http://www.pnas.org/content/100/7/3641 <http://www.pnas.org/content/100/7/3641>
http://www.pnas.org/content/111/3/E306 <http://www.pnas.org/content/111/3/E306>

The following paper lists the experimental pKas of aqua-heme (i.e. HOH vs. HO- as the sixth heme ligand) ranging from 7.6 to 10.8, suggesting that water in its normal form may be the coordinating entity in a significant fraction of cases.  So while the deprotonated thiol and water forms are possibly favored, it is not wrong per se to use the protonated forms.
	Another problematic scenario is when multiple waters are coordinating a metal.  In that situation you definitely would not want to deprotonate more that one of them as per the "Acid–base reactions” section of this page:

Metal aquo complex - Wikipedia <https://en.wikipedia.org/wiki/Metal_aquo_complex>

	In many situations you can get Chimera to protonate atoms as desired by setting the IDATM type beforehand, but for standard residues where the user may often want to vary the protonation state (one of which is cysteine), Chimera(X) ignores the IDATM type and protonates based on the residue name (so CYM for a cysteine with no hydrogen).

—Eric

[tic20@…]

Ok, fair points.

 
 
Tristan Croll
Research Fellow
Cambridge Institute for Medical Research
University of Cambridge CB2 0XY