Drug Target Analysis & Preparation in ICM-Pro

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PDB to ICM Conversion

Objective: convert the PDB to a full atom model for modeling and docking.

• Read in PDB > Search Tab > Enter "1xbb"
• Conversion Protocol: Right-click the object > Convert PDB [00:01:43]
• Atom Completion: ICM automatically builds missing heavy atoms in side chains and adds hydrogens based on internal residue libraries [00:00:22]
• Force Field Assignment: Assigns MMFF atom types, partial charges, and formal charges essential for calculating binding energy [00:00:52]
• Optimization:
  • Hydrogen Network: Global optimization of H-bonding networks [00:00:28]
  • Residue Flips: Asparagine (Asn) and Glutamine (Gln) are flipped to maximize H-bond potential; Histidine (His) protonation is determined by the local environment [00:00:38]
  

• Water Management: Retain "Tight" waters (>3 H-bonds) to maintain structural integrity of the pocket; delete "Loose" waters (0-1 H-bonds) to prevent artificial steric hindrance during docking [00:01:28]

II. Structural Quality Control (QC)

Objective: Quantify the reliability of the atomic coordinates.

• B-Factor: Navigate to Display > click-hold Ribbon > Color by B-Factor [00:03:26]. Warmer colors indicate higher B-Factor greater flexibility.

• Occupancy: Double-click ligand to select it > click-hold Stick in Display Tab > Color by Occupancy [00:03:57]. Low occupancy indicates unreliable atom placement.

III. Electron Density Map Validation

Objective: Direct visual confirmation of atom-to-density fit.

• Map Loading: Tools > X-ray > Get Electron Density Map [00:04:20]
• Contouring: Tools > X-ray > Contour Electron Density Map [00:06:12]
  • 2Fo-Fc Map: Validates current atom placement [00:04:33]
  • Fo-Fc Map: Positive (Green) shows missing atoms; Negative (Red) shows modeled atoms that don't belong [00:04:48]
• Sigma Control: Use '+' and '-' keys. Features should be visible at 1.0–1.5 Sigma [00:05:11]

IV. Handling of Alternative Residue Confirmations

Objective: Understand how to work with alternate residue conformations and save them as separate objects.

• Read in PDB > Search Tab > Enter "1hmt"
• Identification: In high-resolution structures, atoms for a single residue may have two positions labeled 'a' and 'b' [00:08:03]
• ICM Selection Detail: Residues appear with multiple atomic coordinates for the same ID. Toggle or select individually using the 'A' (Atom) selection level [00:08:51]
• The "Clone and Clean" Workflow:
  1. Right-click the residue > Clone. Name it State_A [00:09:10]
  2. In State_A, select the 'B' atoms > Right-click > Delete Atom [00:09:21]
  3. Repeat the process for State_B, deleting the 'A' atoms.
• Outcome: This allows for Ensemble Docking, screening ligands against multiple conformations simultaneously [00:09:37]

V. Symmetry & Biological Reconstruction

Objective: Model the functional unit, not just the crystallographic unit.

• Read in PDB > Search Tab > Enter "1cdg"
• Crystallographic Neighbors: Generate the surrounding crystal lattice pocket via Tools > X-ray > Crystallographic Neighbor [00:10:36]
• Read in PDB > Search Tab > Enter "1al2"
• Biomolecule Generator: Reconstruct full assemblies (e.g., viral capsids) via Tools > X-ray > Biomolecule Generator [00:12:05]