Targeted Protein Degradation (TPD) is an approach that is attracting substantial interest for modulating challenging drug targets. A major class of TPDs are Proteolysis-Targeting Chimera protein degraders (PROTACs). PROTACs are heterobifunctional molecules where two ligands are joined by linker. One ligand recruits the target and the other recruits and binds an E3 ubiquitin ligase. This interaction induces ubiquitylation of the target and degradation by the ubiquitin-proteasome system, the PROTAC is then recycled.

To run PROTAC Modeling use protacModel.icm which is in the /bin directory in the ICM distribution.

icm protacModel.icm <protein1.ob> <protein2.ob> <output.icb> protac=<protacmol.sdf> [<options>]

Options:

• effort= (default effort=1.0 ) Changes Monte-Carlo simulation thoroughness, e.g. effort=3. for more extensive sampling.
• scsRad= (default scsRad=0.0 ) Sample exposed side-chains within this radius from binding moieties, suggested scsRad=8.0
• refstr= For evaluation purposes: calculate PROTAC RMSD versus PDB structure, e.g., refstr=6hax,b,bfwz
• vicinity= (default vicinity=1.0) Change minimum RMSD for a conformation to be considered distinct and stored in the stack.
• number= Take ligand number i from the sd file (e.g. protacmol.sdf) that has multiple structures (single is assumed by default).
• nrun= Run N simulations in parallel and then merge the results using processPROTACsims (see below).

Example

icm protacModel.icm crbn_4ci1.ob brd4_3mxf.ob crbn_brd4_1.icb protac=lig_6bn7.sdf refstr=6bn7,b,brn3 scsRad=8. >& crbn_brd4_1.ou

Results If you undertook multiple runs you will need to process them into one results table. To do this use

processPROTACsims "output_*.icb

Using the wildcard * processes the results from each run and saves them in a single .icb file.

The output.icb will contain the fully interactive results table that can be viewed in the GUI. The complexes are ranked by energy 'ener' column.

• i = rank order
• ener = total energy this is the main score for ranking
• rmsd = RMSD to reference structure (if provided)
• comm = user defined comments as string
• ey = force-field energy
• sf = surface energy term.
• vw = nonbonded interatomic pairwise interactions van der Waals energy.
• el = Electrostatic energy
• EnerSc = Energy of side chains