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Article ID: 874 - Last Modified: September 23, 2013

I would like to run a Desmond mutation FEP calculation on a membrane-bound protein. How can I do this?

You can do this by preparing your model system with a membrane first, then using it to define the perturbation in the FEP panel. This capability was introduced in the 2013-1 release.

Up to Suite 2012, the FEP panels do not allow setup with a membrane. You can do this manually, but it requires editing various files, as described below.

  1. Prepare your protein with the ligand and the membrane with the system builder, then equilibrate it.
  2. Copy the CT of the molecule that you want to mutate from the output .cms file of the equilibration into a separate Maestro file.
  3. Load the new file into Maestro. Include only the molecule to mutate in the Workspace.
  4. Use the appropriate "Mutation by FEP" panel to define the perturbation to the molecule.
  5. In the "Plan Calculation" tab, select only the "in pure solvent" option and then launch a job.
  6. After the system builder stage is done, kill the job. The data of the system builder stage should be returned. The purpose this step is to get the definition of the perturbation in the form of a .cms file.
  7. Extract the -out.cms file from the .tgz file of the system builder stage. This file has several CTs: (1) full-system CT, (2) original-molecule CT, (3) mutant-molecule CT, and (4) a water CT.
  8. Copy CTs (2) and (3) into the your original .cms file (equilibrated membrane system), and delete the old original-molecule CT file.
  9. The full system CT now needs to be fixed

  10. Copy the .cms file to change the suffix to .mae
  11. Import this file into Maestro. The CTs appear as separate entries.
  12. Delete the full-system CT from the project (it should be the first of the imported entries).
  13. Include the remaining entries into the Workspace in the order that they appear in the Project Table (which is the order they were in the file).
  14. Export the Workspace structure to a .mae file (select Workspace for "Structure source to be exported").
  15. Replace the full system CT in the .cms file with the CT from this file.
  16. Delete the system builder stage from the .msj file you generated for the FEP job (the system is already set up).
  17. Run the mutation FEP job with multisim.

Keywords: FEP, membrane, Desmond

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