[Chimera-users] Linking two chains in a PDB file

[Maxwell Cherf]

Hi Elaine,

Using modeller sounds like the exact solution I'm looking for. Both the
ligands and the linker I will connect them with are peptides.

I tried using modeller, but I haven't gotten it to work yet. Here's what
I've done:

1. built peptide linker using the "build structure" function
2. attached the linker to one ligand1 using the "join" function
3. combined the ligand1-linker with the second ligand into one model using
the "combine" function
4. added an unrealistic ~40 angstrom bond between the linker and second
ligand (now we have ligand1 - linker - 40A bond - ligand 2, all in one
model).
5. I then tried using the "model/refine loop" function to find acceptable
orientations for the linker (including the 40A bond) I incorporated, but I
was unable to do this because the two ligands were still separate chains,
and the "model/refine loop" function requires them to be in the same chain.
If I use the "join" command instead of the "combine" command to attach the
ligand1-linker to ligand2, I get one chain and then the model/refine loop
function works perfectly to remodel the linker. However, using the join
function changes the orientation of the ligands relative to the receptor,
and I need the ligands to remain docked properly to the receptor.

Is there a way to join both ligands into the same chain without changing
their orientation? Or, do you know of an alternate approach for adding a
linker between the two ligands without changing their orientation using
modeller?

Thanks again,
Gerald







On Fri, Aug 9, 2013 at 4:31 PM, Elaine Meng <meng at cgl.ucsf.edu> wrote:

> Hi Gerald,
> Yes, but ... probably not without making the structure very bad, in a way
> that may or may not be rescuable.  You can add a bond between two atoms
> that is 50 angstroms long if you want, with Build Structure or the "bond"
> command.  (The two atoms have to be in the same model before you can bond
> them.)  You could even try rotating torsions within the linker manually to
> try to make the other end of it closer to the desired destination point.
>  In my experience, however, trying to manually fulfill multiple constraints
> (reasonable phi/psi as well as endpoint locations and not running into
> other atoms) is extremely difficult and frustrating.  You could try
> energy-minimizing the result, maybe even letting only the atoms within the
> linker move.  Again caveats: minimization has extremely limited ability to
> improve a mangled structure, as it will only go "downhill" and not climb
> even small barriers that need to be surmounted on the way to a reasonable
> structure.  It depends whether there is clear downhill path to a reasonable
> structure, and this may not be the case for any complicated building.
>
> In my opinion, modeling like this is better done with software that
> performs conformational sampling (dynamics or just combinatorics) in the
> presence of constraints and/or restraints.
>
> It also depends on what you plan to do with the result; if it's just going
> to be a schematic, you would worry less than if you are trying to do
> something quantitative like rationalize binding affinities.
>
> If everything were peptidic (i.e. ligand + linker + ligand = one peptide)
> perhaps it could be done with Modeller's loop-building capability.  In
> other words, Modeller could propose multiple linker conformations as if it
> were a loop between the peptides on either end.  You would give it the full
> sequence and it would fill in the gap with possible structures.  Chimera
> includes interfaces to Modeller:
> <
> http://www.rbvi.ucsf.edu/chimera/docs/ContributedSoftware/multalignviewer/modeller.html
> >
>
> However, it sounds like your ligands are organic molecules but not
> peptides.  Sorry I couldn't give a rosier picture,
> Elaine
> -----
> Elaine C. Meng, Ph.D.
> UCSF Computer Graphics Lab (Chimera team) and Babbitt Lab
> Department of Pharmaceutical Chemistry
> University of California, San Francisco
>
> On Aug 9, 2013, at 1:44 PM, Maxwell Cherf wrote:
>
> > Hi Elaine,
> >
> > Thank you for your reply! I was able to attach both ligands using the
> split command followed by the join command.
> >
> > I have another problem now though -  my goal is to build a peptide
> linker that attaches the termini of two ligands that are bound to a
> receptor (the PDB contains three protein structures) ; I also want both
> ligands to remain properly docked to the receptor while I incorporate the
> linker. Using the slit/join commands allowed me to link both ligands, but
> ended up changing their orientation relative to the receptor. Is there a
> way to build a peptide linker that attaches the termini of the two ligands
> without changing their orientation using Chimera?
> >
> > Thanks again,
> > Gerald
>
>
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