Feb 16 2024 Feedback.
Contents
 
Introduction
Help Videos
Reference Guide
Getting Started
Protein Structure
Molecular Graphics
Slides & ActiveICM
Sequences & Alignments
Protein Modeling
Cheminformatics
Learn and Predict
Docking
 Small Molecule Docking
 Flexible Docking
 Template Docking
 Covalent Docking
 Autofit
 Peptide Docking
 Protein-Protein Docking
 PROTAC
Virtual Screening
Molecular Dynamics
MolScreen
3D Ligand Editor
Tables and Plots
Local Databases
ICM-Scarab
KNIME
Tutorials
FAQs
 
Index
PrevICM User's Guide
12.8 PROTAC Modeling
Next

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.
The MolSoft ICM PROTAC modeling method:
  • Start with structures of target protein and cereblon or VHL complexes with their respective binding ligands/moieties
  • PROTAC molecule is modeled into first complex and then into second complex using ligands as templates
  • Internal coordinate MC simulation sampling linker torsions optimizes tripartite complex
  • Surrounding sidechains also flexible
  • Resulting ensemble of low energy conformers is re-evaluated using scoring function optimized for protein-protein docking
| Watch a Webinar on PROTAC Modeling|

The ICM PROTAC modeling method:

  • Start with structures of target protein and cereblon or VHL complexes with their respective binding ligands/moieties
  • PROTAC molecule is modeled into first complex and then into second complex using ligands as templates
  • Internal coordinate MC simulation sampling linker torsions optimizes tripartite complex
  • Surrounding sidechains also flexible
  • Resulting ensemble of low energy conformers is re-evaluated using scoring function optimized for protein-protein docking

How to Run PROTAC Modeling - Example Bromodomain-Cereblon PROTAC: Setup

  • Read into ICM the target PDB Bromodomain "3mxf" and Cereblon "4CI1".
  • Delete molecules that are not needed - you should have just the ligand and receptor for both the target and cereblon. To delete hold "CTL" button and left click on the molecules you want to delete - then right click and choose delete.
  • Convert both PDBs into an ICM object.
  • Prepare the PROTAC molecule you want to dock - you can sketch it, read in a mol file or extract it from a PDB. In this example we extract the PROTAC in pdb "6bn7" which is the Bromodomain-Cereblon-PROTAC complex.

Run PROTAC Modeling

  • Docking/Protein-Protein Docking/PROTAC Model Builder
  • Select the target and Ligase object from the drop down button. In this example target=a_3mxf. ligase=a_4ci1.
  • Enter the name of the table that contains your PROTAC. Molecule index= row number if you have multiple PROTACS in the table.
  • Effort is the length of the simulation and changes Monte-Carlo simulation thoroughness (length of simulation) , e.g. effort=3. for more extensive sampling. If you are running five parallel runs then effort=1. is fine.
  • Enter the number of parallel runs - we recommend 5 runs.
  • Optional. For evaluation purposes: calculate PROTAC RMSD versus PDB structure, e.g., for this example we can compare with the Bromodomain-Cereblon-PROTAC complex pdb 6bn7 'b' chain and name of protac molecule 'brn3' so enter: 6bn7,b,brn3.
  • Click OK to run the simulation.

Results When the simulation has finished a dialog box will be displayed asking you to display the results. Click OK and a table of the results will be displayed. Single click on a row and the PROTAC complex will be displayed and loaded into the ICM Workspace (left hand side panel). The complexes are ranked by the energy column 'ener'.

  • 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
  • deltaSurf = deltaSurf is the solvent-accessible surface area buried between the two proteins (the degrader small molecule is not included in this calculation)
  • EnerSc = Energy of side chains


Prev
Refinement
Home
Up
Next
Small Molecule Docking

Copyright© 1989-2020, Molsoft,LLC - All Rights Reserved.
This document contains proprietary and confidential information of Molsoft, LLC.
The content of this document may not be disclosed to third parties, copied or duplicated in any form,
in whole or in part, without the prior written permission from Molsoft, LLC.