[chimerax-users] Refine predicted structure by pulling

[Tom Goddard]

Hi Roden, Tristan,

   I tried Tristan's suggestion for straightening the long AlphaFold 
helix model.  It didn't work well for me because the restraints were too 
soft, so if I pulled on the first 160 residues it hardly moved the 
attached 2000 and instead just distorted the linker.  Tristan is there a 
way to make the restraints much stiffer?  I see the "isolde restrain 
distance" command has a "kappa" option and "falloff" option but I don't 
know if kappa is a stiffness or what magnitude it usually uses.

   I think a better approach is to just rigidly rotate and translate 
large straight sections by hand using the "Move atoms" mouse mode in the 
ChimeraX 1.3 toolbar tab called Right Mouse.  I tried this and have 
attached an image of about 10 minutes fiddling by hand.  I hover the 
mouse at a hinge residue to get the residue number and then select 
everything on one side of that hinge "select :1182-2419" then use the 
right mouse button in the "move atoms" mode, holding the shift key down 
to do rotations, and no shift key to do translations.  I zoom in on the 
hinge to try to adjust so the bond is not stretched and to avoid 
clashes.  It would probably take 1 hour to do a good job.  With my 10 
minute test I then saved an mmCIF file and tried in ChimeraX 1.2.5 to 
minimize it with ISOLDE, but it said there were severe clashes.

     Tom



On 10/24/2021 1:49 AM, Tristan Croll via ChimeraX-users wrote:
> Hi Roden,
>
> This should be reasonably straightforward with the ISOLDE plugin 
> (https://cxtoolshed.rbvi.ucsf.edu/apps/chimeraxisolde 
> <https://cxtoolshed.rbvi.ucsf.edu/apps/chimeraxisolde>). You'll also 
> want to be working on a machine with a good GPU to make it feasible 
> for a model this size. It'll be easier still with the new release 
> coming in a few weeks, which has some added tools specifically for 
> working with AlphaFold models. But with care you could do it now:
>
>   * first, check carefully for entanglement between distant domains
>     (this is an issue for AlphaFold with these very long, flexible
>     proteins - if distant parts of the protein have no coevolutionary
>     signal they don't really "know" about each other and can end up
>     trying to occupy the same space). Looks like your particular
>     example is free of that problem.
>   * Start ISOLDE. Then, assuming your protein is model #1, do the
>     following commands:
>       o isolde restrain distances #1 distanceCutoff 5
>       o isolde restrain torsions #1 angleRange 60
>       o isolde sim start #1
>   * Then, you'll want to use the "tug selection" mouse mode (third
>     from bottom right of the ISOLDE panel). Make a selection for a
>     suitable region to tug (e.g. "sel #1-100 at CA" to tug the
>     N-terminus), and tugging forces applied by right-click-and-drag
>     will be spread over that selection. Keep a close eye on the
>     distance restraints - if they start to become too strained (lots
>     of purple appearing), stop tugging and let the model settle.
>   * If you have unwanted distance restraints between domains that
>     should be distant from each other, you can selectively release
>     restraints on selected atoms with "isolde release distances sel".
>   * You might find it easier for a job like this to reduce the view to
>     a C-alpha trace - just "hide ~@CA" - if you do this after you've
>     started a simulation, it'll automatically revert to the all-atom
>     view once you stop.
>
> Happy modelling!
>
> -- Tristan
>
> ------------------------------------------------------------------------
> *From:* ChimeraX-users <chimerax-users-bounces at cgl.ucsf.edu> on behalf 
> of Roden Deng Luo via ChimeraX-users <chimerax-users at cgl.ucsf.edu>
> *Sent:* 23 October 2021 16:30
> *To:* chimerax-users at cgl.ucsf.edu <chimerax-users at cgl.ucsf.edu>
> *Subject:* [chimerax-users] Refine predicted structure by pulling
> Dear ChimeraX Users,
>
> There is this AlphaFold prediction: 
> https://alphafold.ebi.ac.uk/entry/P02549 
> <https://alphafold.ebi.ac.uk/entry/P02549>. And we know this protein 
> should be more or less in a rod-like shape rather than a globular 
> shape: https://en.wikipedia.org/wiki/Spectrin 
> <https://en.wikipedia.org/wiki/Spectrin> and related literature such 
> as https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218374/ 
> <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218374/>. I wonder is 
> there a way that we can pull the two ends of the predicted structure 
> while maintaining the secondary structures, mostly alpha-helices in 
> this case, inside ChimeraX?
>
> I am quite new to ChimeraX. I understand this is more fitted to an MD 
> simulation. But I got to know there are options to fit a PDB to a 
> density map. So I wondered if this can be achieved in ChimeraX.
>
> Best,
> Roden
>
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