FEP+ for GPCR
2/25/2021 Ying Yang
Steps for setting up a FEP prediction for membrane protein
Protein side
Carefully look into the binding site and make sure the residues are correctly protonated...
Protein model completeness Protein preparation should include fixing any chain breaks, modeling in any loop conformations and adding any missing side chains. Chain breaks near the active site will likely lead to poor results. Disulfide bridges should be created and termini residues capped where applicable.
Equilibration of complex structure (with confident binding pose)
- Build membrane (use the OPM database), add salts, add solvent
res.num 76-97,112-136,141,143,146-171,194-215,227-229,231-256,323-345,347,360-380,382,398
- write job submission file, and replace gimel-biggpu to gimel5.heavygpu
sed -i 's/gimel-biggpu/gimel5.heavygpu/g' desmond_md_job_1.sh
- Transfer (scp) to gimel5, and submit
bash desmond_md_job_1.sh
- Kill a submitted or running job:
$SCHRODINGER/jobcontrol -kill <jobID>
- Analyze the MD simulation
Visualize the trajectory and analyze the simulation with SID tool
- Convert -out.cms into mae
$SCHRODINGER/run membrane_cms2fep.py -ligand 'ligand' 2A_NBOH_MD-out.cms -o relax_2A_NBOH_pv.mae
Ligand side
Careful preparation of the ligands is critical to a successful FEP+ prediction. Best practices include running LigPrep on all the compounds to exhaustively enumerate all the stereoisomers and likely protonation states of the ligands. Note that triply-substituted ammonium cannot invert stereochemistry during the simulation, making it important to model both pseudo-stereoisomers.
- Force field builder
Run force field builder for all ligands
- Flexible ligand alignment OR core constrain docking
Depends on how similar/different are the ligands to the reference/center ligand
- Create FEP maps
- Write out the submission file; change host; submit on gimel5 via slurm