Peptide Modeling & Editing in the 3D Ligand Editor

Video Structure Overview

• 0:00 - 3:17: Introduction to the method, benefits of continuous chain handling, peptide mode, and setup concepts. [Watch intro]
• ~3:17 - 11:31: Hands-on demo - loading/merging, setup, editing, refinement, stapling, scoring, and variants.

Purpose

Model, edit, refine, staple, and score peptides (including helical and stapled peptides) using sequence-level tools with continuous chain handling.

Key Module

Interactive Ligand Editor (peptide mode)

Prerequisites

• MolSoft ICM-Pro installed
• A peptide structure (e.g., PDB file like 7UWI)
• Optional: stapled peptide components

Step-by-Step Instructions (Demo-Focused)

1. Initial Setup in Demo [~3:17 - merge/convert]

1. `quick-start-read-pdb{Import} peptide PDB (e.g., 7UWI).
2. If separate: merge peptide + staple/linker -> right-click on the linker in the ICM workspace -> "Merge into Covalent Parent" [~3:30]
3. `converting-pdb{Convert} to ICM object format -> "Convert to ICM" [~3:45]
4. Launch Interactive Ligand Editor by clicking on the LigEdit Tab
5. Click on setup peptide -> enable Peptide Mode (toggle/checkbox) [~4:00]
6. Click on setup receptor button - select define site around selected ligand.

Purpose: Enables continuous chain, correct backbone geometry, sequence-level editing.

2. Basic Peptide Sequence Editing [~5:00 onward]

Use sequence viewer/editor panel:

• Delete residue(s) (e.g., disordered C-term) -> select -> delete [~5:23]
• Add terminal caps: Acetyl (N-term) or NH₂ (C-term) -> right-click terminal -> Modify [~5:38]
• Insert residue (e.g., Glycine at C-term) -> position cursor -> insert [~7:23]
• Replace residue (e.g., Leu6 -> Ile or to extended/non-standard) -> select -> replace [~7:50]

Edits preserve chain continuity and auto-update geometry in Peptide Mode.

3. Geometry Refinement and Stabilization [~6:00 onward]

1. Relax -> fixes clashes and covalent geometry (run after edits) [~6:00]
2. Reinforce Helix -> tightens alpha-helical regions [~6:02]
3. Minimize torsions/side chains -> optimize individual residues -> right-click -> Optimize Residue [~6:07]

4. Monitoring Model Quality - Real-Time Scoring [~6:00+ ongoing]

Watch (lower = better; strain <15 reasonable):

• RTCNN score - neural network-based structure quality/fit
• LigStrain - internal strain energy

Scores update live during edits/refinement.

5. Adding Peptide Staples [~10:00 onward]

1. Select residue -> right-click -> "Install Staple" (library: hydrocarbon I+4 or I+7, specialty) [~10:09] for I+7 example
2. ICM auto-finds partner residue -> forms covalent bridge [~10:30]
3. Re-run Relax/minimization -> use eraser tool for leftover atoms if needed [~10:46]
4. Check updated RTCNN + LigStrain

Custom staples: contact MolSoft (info@molsoft.com).

6. Advanced Modifications [~9:12 onward]

• Residue-level: mutate, optimize rotamer
• Atom-level: manual tweaks (e.g., change C -> O for better H-bond) [~9:12]
• Use interactive table: Add to Table -> save variants -> undo/redo -> reload/compare by double-click

Tips & Best Practices from the Demo

• Enable Peptide Mode -> avoids broken chains or incorrect geometry
• Run Relax after insertions/deletions/replacements/stapling
• Use Reinforce Helix for helical peptides before final scoring
• Monitor RTCNN + LigStrain live to guide favorable changes
• Full undo/redo + table history makes experimentation safe
• Example structure: PDB 7UWI (Beta-Catenin + Helicon stapled peptide)

Additional Resources

• Support: support@molsoft.com
• Example PDB: 7UWI