Homodimer interface design

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    • #1465


        I am trying to use RosettaDesign or (preferably) enzdes to redesign a defined interface. I would like the interface to be homodimeric. Can symmetry be invoked in enzdes or RosettaDesign to ensure that both monomers are mutated simultaneously? If so, is there a guide to this?

        – Igor

      • #8107

          I’m not quite sure why you would prefer to use enzdes for the protocol, but there are certainly ways of designing symmetric interfaces in Rosetta. See King et al. Science. 2012 336(6085):1171-4. for an example.

          The big caveat is that a number of things in Rosetta are symmetry un-aware. With the materials and symmetric design push in the Baker lab recently, this has been fixed for many things, but unfortunately most of these fixes haven’t been released yet.

          Here’s what Jacob Bale (who works on symmetry) forwarded to me as an example of a simple symmetric design protocol:

          1) Generate a symmetry definition file:
          – This can be done using the make_symmdef_file.pl script (located at rosetta/rosetta_source/src/apps/public/symmetry/make_symmdef_file.pl):
          See http://www.rosettacommons.org/manuals/archive/rosetta3.4_user_guide/db/d1b/make_symmdef_file.html for details
          Note: This requires that you have your symmetric (or close to symmetric) structure as input.
          2) Compile a rosetta_scripts executabale
          3) Run the following command (adjust executable and database as appropriate) providing your assymetric unit (just chain A in the case of a homodimer) as input

          ~/rosetta/rosetta_source/bin/rosetta_scripts.linuxgccrelease -database ~/rosetta/rosetta_database/ -parser:protocol C2_3.4_compatible.xml -ex1 -ex2 -out:path:all -nstruct 1 -s assymetric.pdb

          Note that you can adjust the attached xml script to do more complex things with the movers/filters/taskoperations at http://www.rosettacommons.org/manuals/archive/rosetta3.4_user_guide/RosettaScripts_Documentation — but keep in mind that many of them might not be symmetry aware, and so might not work or might not work as expected.

        • #8111

            Thanks! I was asking about enzdes because I have a metal binding site at the interface that I need to preserve – I was going to use a cst file. But, I can get away with Design if I can figure out how to make those residues involved in binding non-designable.

            Can a resfile be used to define designable positions like in standard design? Also, does this script necessarily enforce symmetric packing or just symmetric mutation? In my case I don’t necessarily care that the packing is exactly symmetric, just the design.


          • #8113

              You can certainly load enzdes style constraints with RosettaScripts – just use the AddOrRemoveMatchCsts mover to add them to the pose prior to the design/repack/etc. steps you want to use them with (See RosettaScripts docs for more info). I’m not sure quite how well they play with symmetry – you may have to limit yourself with making constraints to the single asymmetric unit, rather than to both sides of the symmetric interface.

              Limiting residues which you design is as simple as figuring out which task operations to use. You can either specify them in the XML with some combination of OperateOnCertainResidues operations, or probably easier you can load them from a resfile with a ReadResfile task operation (see docs for details). Just add the additional task operation to the comma separated list in your design mover specification. Keep in mind that combining task operations is restrictive – each residue gets the most restrictive behavior, so the default property in your Resfile should be ALLAA so the RestrictToInterace restricts the rest.

              The script I gave enforces true symmetry – in design, packing, and minimization. There’s some new code (“rotamer links”) which can enforce identity coordination without true symmetry, but I don’t think that’s in the released code yet.

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