Workshop: Molecular Dynamics (MD) in ICM-Pro

I. Foundational MD Setup & Execution

Objective: Perform standard MD simulations to observe protein-ligand stability and local conformational changes.

• System Preparation: Load your structure and convert it to an ICM object via Right-click > Convert PDB [00:12:15]. ICM assigns Amber force field parameters to the protein and handles chemical completion [00:03:56].
• Configuration in GUI: Navigate to MolMechanics > Run MD Simulation [00:12:29].
  • Solvation: Explicitly solvate the system to fill the simulation box with water [00:02:59].
  • GPU Optimization: Enable GPU support (OpenMM) to achieve rates up to 1 μs per day on standard workstations [00:00:29].
• Trajectory Management: Snapshots are stored in an ICM Confirmational Stack [00:01:23]. Visualize hinge movement and pocket fluctuations by playing the stack as a movie [00:13:26].

II. Specialized Workflows: Membranes & PROTACs

Objective: Addressing high-complexity systems using specialized OpenMM integrations.

• Membrane Simulation: Select the Membrane tab in the MD dialog [00:04:32]. Uses a membrane-compatible barostat to maintain lateral pressure without distorting the bilayer [00:06:14]. Includes a compaction step to remove vacuum gaps or trapped water bubbles [00:06:58].
• PROTAC Refinement: Refine tripartite complexes using multiple independent trajectories (e.g., five 100 ns runs) [00:08:38]. Monitor the transition toward the native state using 2D trajectory maps [00:10:06].

III. Enhancing Virtual Screening (Hit Validation)

Objective: Use MD as a secondary filter to identify and remove dynamically unstable hits.

• Scripting the Validation: Use the run_md_openmm.icm script in the /bin directory [00:02:33]. The script applies NN AM1 BCC charges and restrains ( -RL ) regions far from the binding pocket [00:03:06].
• Analyzing the MD Summary Table:
  • RMSD0: Measures the drift from the initial docked pose. High drift suggests an unstable binder [00:09:17].
  • TV (Time Covariance): Indicates continuous drift; lower values mean the pose stabilized quickly [00:10:22].
• Calculation Tools: Right-click the stack > Stack Calculations [00:05:01]. Calculate GBSA delta G binding estimates, RTCNN scores, and Ligand Contacts [00:05:40], [00:14:17].