Workshop Guide: Peptide Modeling in the Ligand Editor

Based on the MolSoft ICM-Pro tutorial: View Video Here

1. Loading and Preparing the Structure

• Search and Load PDB: Search for PDB entry 7UWI (Beta-catenin bound to a helical peptide). [03:18]
• Merge Covalent Components: If the staple and peptide appear as separate molecules, right-click and select Merge into Covalent Parent. [03:41]
• Convert to ICM Object: Right-click the object name and select Convert PDB, using default options to prepare it for modeling. [03:48]

2. Setting Up the Ligand Editor

• Enter Peptide Mode: In the Ligand Edit tab, click Setup Ligand and ensure Peptide Mode is selected. [03:57]
• Setup Receptor: Click Setup Receptor and choose Make box around existing ligand to define the simulation area. [04:08]
• Visual Refinement: Use the Pretty View button and switch the peptide display to Ribbon or Smooth for clarity. [04:36]

3. Sequence & Residue Editing

• Delete Residues: Right-click disordered residues and select Delete Residue. [05:21]
• Add Terminal Caps: Select a terminal residue and choose Add Modifier to attach caps like Acetyl or NMe. [05:33]
• Insert Residues: Right-click a position to Insert Residue (e.g., adding Glycine spacers). [07:03]
• Replace/Mutate Residues: Use Replace Residue > Extended to access a library of non-natural amino acids. [08:16]

4. Optimization and Scoring

• Relax Geometry: Use the Relax tool to resolve clashes and optimize bond angles. [05:48]
• Refine Helices: Use the Reinforce Helix tool to stabilize alpha-helical segments. [05:54]
• Monitor Quality: Check the RTCNN Score and Strain metrics; lower values indicate a more favorable model. [06:04]

5. Peptide Stapling

• Install Staple: Right-click a residue and select Install Staple to automatically bridge to an i+4 or i+7 partner. [10:04]
• Custom Modifications: Interactively change atoms using the chemical side panel and re-minimize to evaluate binding. [09:10]

6. Iteration and Data Tracking

• Save to Table: Click Add to Table to store a snapshot of your design and its associated scores. [06:42]
• Compare Designs: Double-click any row in the table to instantly reload that specific peptide variant. [11:17]