[chimerax-users] Modeling post-translational modifications

Thu Apr 13 00:37:53 PDT 2023

Wonderful, thank you Tristan! Even this "good enough hack" is out of reach with my skillset, so this is much appreciated.

Out of curiosity, what are the "more general approaches on the horizon"?

Guillaume

On 12 Apr 2023, at 13:30, Tristan Croll <tcroll at altoslabs.com<mailto:tcroll at altoslabs.com>> wrote:

Oh, I wish there were good central databases for such things - but unfortunately (in my experience at least) everything is still quite fragmented. I don't know of any good automated tools for parameterisation of residues that make covalent bonds to others - ANTECHAMBER (the official AMBER ligand-parameterisation tool ISOLDE uses to parameterise free ligands) uses its own set of atom types (the General Amber Force Field, or GAFF) that aren't designed to link to the protein or nucleic acid force fields. But for relatively simple cases like this that only use existing atom types it's possible to hack together something "good enough" (at least for working in reasonable density, not necessarily for equilibrium simulations) by using ANTECHAMBER to parameterise the free KCX "ligand" to get charges, then hand-merge the result with the existing LYS template - translating GAFF types back to the equivalent protein force field types and making gentle adjustments to the charges to ensure the residue has an overall integer charge. Not exactly elegant, but I'm not really keen to put a huge effort into this aspect of things when there are much better and more general approaches on the horizon. I've done that for KCX (since it really should be in ISOLDE's core force field anyway) - the attached .xml should get you going.

On Wed, Apr 12, 2023 at 9:11 AM Guillaume Gaullier via ChimeraX-users <chimerax-users at cgl.ucsf.edu<mailto:chimerax-users at cgl.ucsf.edu>> wrote:
Thank you Tristan and Elaine,

For now, I will go with Elaine’s option A. But this recipe with ISOLDE is good to know too!

This brings new questions: are there central databases for MD parameters and rotamer libraries? If so, can simple users like me learn how to add entries to them? (of course assuming submissions are curated by experts; I would not want my additions to be directly available to every ChimeraX user without prior review).

Thank you again.
Cheers,

Guillaume

On 11 Apr 2023, at 18:05, Elaine Meng <meng at cgl.ucsf.edu<mailto:meng at cgl.ucsf.edu>> wrote:

Hi Guillaume,
In general, rotamer libraries do not include nonstandard residues or even standard residues with PTMs. So, there is no built-in single step way to replace a residue with one of those in ChimeraX.   Some possibilities with more steps are:

(A) start with lysine at that position, and then build on the N-carboxylate (a few steps of modifying and adding individual atoms) e.g. using Build Structure tool, the Modify Structure section.
<https://rbvi.ucsf.edu/chimerax/docs/user/tools/buildstructure.html>

(B) with the "align" command, match some of the KCX atoms onto the corresponding lysine atoms (backbone or part of sidechain, whatever works in your situation), save PDB of the KCX atoms "relative to" the model onto which it was just matched, then using a text-editor on these two resulting PDB files, manually replace the lysine sidechain atoms from the original structure with the KCX sidechain atoms.  You would also want to change the residue name to KCX in this text-editing process.
<https://rbvi.ucsf.edu/chimerax/docs/user/commands/align.html>
<https://rbvi.ucsf.edu/chimerax/docs/user/formats/pdbintro.html>

(C) sometimes depending on the specific modification, the unnatural amino acid will be available in the SwissSidechain database.  In that case, you can use the SwissSidechain plugin available for Chimera (not ChimeraX).
<https://swisssidechain.ch/visualization/chimera.php>

However, I looked in that database in the lysine derivative section and it does not have lysine N-carboxylic acid (KCX)
<http://ligand-expo.rcsb.org/pyapps/ldHandler.py?formid=cc-index-search&target=kcx&operation=ccid>
<https://swisssidechain.ch/browse/family/table.php?family=lysine>

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 11, 2023, at 7:26 AM, Guillaume Gaullier via ChimeraX-users <chimerax-users at cgl.ucsf.edu<mailto:chimerax-users at cgl.ucsf.edu>> wrote:

Hello chimerax-users,

I am trying to model a PTM, and the most sensible way to me seems to use the swapaa command and specify the sensible monomer from the PDB Chemical Component Dictionary as the target residue.

Here is what I tried (residue #1/a:9 is a Lys):

open 1kx5
swapaa #1/a:9 KCX

And the error I got: Dynameomics rotamer library does not support KCX

I tried all the rotamer libraries listed in the swapaa help page ( https://www.cgl.ucsf.edu/chimerax/docs/user/commands/swapaa.html#rotLib ), but none of them can provide stereochemical info for KCX.

I can open the monomer I want (carbamylated Lys) with: open ccd:KCX
But of course in this case it’s floating by itself as a new model, not incorporated in the protein sequence and structure I am interested in.

Is this the correct way to model a PTM? If it is, where can I find a rotamer library that will contain the stereochemical info for KCX, and how do I tell ChimeraX to use it? If it is not how modelling a PTM is done, then how else should I do this?

Thank you in advance,

Guillaume

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<KCX.xml>

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