I have sent Abdulrahman a separate message, but I'll add it here (stripped
of the major MOE points that are not relevant to most people on this list)
because it might be useful for other people:
Always check your structure, always choose appropriate structure preparation
before sinking any resources (your time, compute time, electricity) into
the project.
-Sarah
-----
- It is very important to consider (1) which crystal structure to use
and (2) the uncertainty for the structure you end up choosing.
- MOE has tools for all structure preparation, protonation, parameter
derivation, solvation, and writing out .prmtop and .coor files for Amber.
Not only is there no need to use all sorts of different software, but
you also risk running MD to check the stability of a docking pose made on
one structure, but the MD is a different structure (different protonation
states, etc.).
The crystal structure *3FHD *has several missing residues:
- 28 missing residues at the N terminal
- 5 missing residues at the C terminal
- 4 missing residues between Cys314 and Arg319
- 16 missing residues between Ser163 and Gly180
You can see this is MOE by using the panel *(MOE | Protein | Structure
Preparation)*: This panel will list all the issues in a structure and also
allow you to deal with them.
You can also see this at the *Structure* tab of the RCSB entry (
https://www.rcsb.org/3d-view/3FHD).
In your case, your docked ligand is placed close to the 16-residue missing
loop, which means that the docking site isn't well defined and that you
won't capture all the long-range non-bonded interactions. You will need to
consider whether you still find it reasonable and useful to dock a ligand
to this structure at this position. You may choose to use the structure,
but then you need to be aware of the high degree of uncertainty found in
the docked site. If you do use the structure for docking, please make sure
you cap the gap residues rather than protonating the protein backbone NH on
Gly180 and convert the C=O Pro164 backbone into COO-, since the actual
protein wouldn't have these charges here.
For MD, you should not leave the protein with gaps in the sequence: The
4-residue and 16-residue gaps will, in effect, break the protein into 3
separate chains, which could lead to a very different behaviour in MD.
On Mon, Mar 30, 2026 at 7:02 PM ElBagoury, Abdulrahman Walid Attia Ibrahim
via AMBER <amber.ambermd.org> wrote:
> Thank you for clarifying this and I will try it as well. I also appreciate
> both the video and your article with the quick tips.
>
>
> Finally, regarding the usage of the Modeller part, should I perform this
> step prior to the docking and MD simulation protocols that I previously
> provided?
>
>
> Also, concerning my previous protocol, are the steps in the correct order,
> and would it be appropriate to proceed with this workflow, or would you
> recommend any modifications?
>
>
> Best Regards,
> Abdulrahman
>
>
>
>
>
>
> Abdulrahman Walid Attia Ibrahim ElBagoury
> Antivirale und Antivirulenz-Wirkstoffe
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> ________________________________
> From: Téletchéa Stéphane via AMBER <amber.ambermd.org>
> Sent: Monday, March 30, 2026 7:04 PM
> To: amber.ambermd.org
> Subject: Re: [AMBER] [EXTERN] Re: Ligand Prepartion
>
> Le 30/03/2026 à 17:02, ElBagoury, Abdulrahman Walid Attia Ibrahim via
> AMBER a écrit :
> > At this step, I encounter an error indicating a backbone gap between CYS
> A 314 and ARG A 319, and pdb2pqr stops because the biomolecular structure
> is incomplete. However, when I run pdb2pqr on the original PDB file (before
> docking/export from MOE), the protonation runs without any errors.
> Dear all,
>
> This is a classical error with PDB files with missing residues, which is
> very often with PDB files,
> for many reasons, one being for instance the lack of experimental support.
>
> It is not an issue when you docking only, since most of the time the
> protein is kept rigid,
> and probably the residues involved in the binding are not those of the
> missing part.
>
> You should complete your pdb file using MODELLER for instance, you can
> do it in Chimera:
> https://rbvi.ucsf.edu/chimerax/data/loop-modeling/loop-modeling.html
>
> I found also videos of this (not mines) if that helps:
> - https://www.youtube.com/watch?v=GV6jHhxR5T4
> - (and many others).
>
> This should not change a lot the conformation and/or the binding site (I
> assume not),
> but will solve the problem for AMBER modelling.
>
> To be complete, we set up a series of "quick tips" last year, to help
> people getting
> through these problems and questions more easily:
>
> https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1013030
>
> We'll submit another article this year covering more specifically the
> problem you are facing,
> as it is quite common and a bit disturbing while being alone to find a
> solution.
>
> HTH,
>
> Stéphane
>
> --
> Maître de conférences Hors Classe, PEDR, HDR
> US2B, Nantes Université, CNRS, UMR 6286, Team Structural Bioinformatics,
> F-44000 Nantes
> http://www.us2b.univ-nantes.fr/ - http://www.steletch.org
>
>
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Received on Wed Apr 01 2026 - 04:00:02 PDT
