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I'm working on running simulations of human topoisomerase IIa. These are best done by starting with high resolution structures to ensure the system is as accurate as possible. However, no crystals exist of the full TOP2A structure (catalytic & DNase domains).

What do exist are high resolution crystals of the separate catalytic and DNase domains and low res complete structures.

Is there a way, through simulations or otherwise, to impose the high resolution structural information onto the lower resolution full protein model?

Low-res full cryo-EM structure (~8 A)

enter image description here

High-res partial crystal structure (~2 A)

enter image description here

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  • $\begingroup$ Not sure you’ll find an answer here. Quite a high-power question for this very broad group. If not, you might try SE Bioinformatics, although they tend to be more nucleic acid oriented. But you really need to talk to experienced protein structure people. Bite the bullet and email a biggie. $\endgroup$
    – David
    Dec 20, 2022 at 19:36
  • $\begingroup$ seems related, may be applicable: pnas.org/doi/10.1073/pnas.1506788112, academic.oup.com/bioinformatics/article/23/19/2558/185859, "fragment assembly" here: nature.com/articles/s41580-019-0163-x $\endgroup$ Dec 21, 2022 at 0:50
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    $\begingroup$ @MaximilianPress Thanks for the articles! I'm actually very familiar with the nature pub you linked and its relevant, but tangentially! I will look into them, but I've found a few potential solutions that fall into the approach of "Hybrid Structure Modelling/Refinement". I'm looking into using a software I'm semi-familiar with, Chimera, that apparently has this capability. I'll report back here if it works out! $\endgroup$
    – Paul
    Dec 21, 2022 at 5:23
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    $\begingroup$ @Paul yes please answer your own question if you can! It seems like something that would be of interest to a lot of people. $\endgroup$ Dec 21, 2022 at 5:29
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    $\begingroup$ Don’t cross-post. It’s frowned upon on SE. $\endgroup$
    – David
    Dec 21, 2022 at 8:13

1 Answer 1

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You should use the original electron density map, not the atomic coordinates associated with it.

Other than that, what you are describing is fairly routine. Briefly, the high resolution structure is used as the starting point for a simulation, the atoms are moved around using the low-resolution information as a potential energy field, and the motion of the atoms is constrained with a level of granularity chosen by the user. I use the "Real Space Refine" program in the package PHENIX, but if you are familiar with VMD, you might prefer their flexible fitting plugin. Chimera can do "rigid body fitting" well, but that's not ideal unless you're certain the low-resolution and high-resolution structures are both of the exact same molecules.

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