A frequent challenge in molecular modeling is preparing a protein–ligand system for unbinding pathway simulations. Even experienced users often encounter issues with misassigned atoms or poorly defined conformations, which can invalidate simulation results.
Fortunately, the Ligand Path Finder app in SAMSON provides a structured approach to set up your system correctly. In this post, we’ll highlight critical steps and tips to set up a system that works reliably with methods like ART-RRT.
Why System Setup Matters
Ligand unbinding simulations are sensitive to the structure and state of the molecular system. If the system is not properly prepared—say, with poorly defined ligand atoms or a misaligned sampling region—the exploration of pathways may be inefficient, inaccurate, or even fail entirely. Let’s walk through how to build a solid base for your unbinding simulations.
Start with a Properly Minimized Conformation
Begin by loading a minimized conformation of your protein-ligand complex. In the Ligand Path Finder tutorial sample, this means selecting the bound_minimized conformation and clicking Set in the app. This ensures that your starting point is structurally stable.
Clearly Define Ligand and Protein Atoms
Next, select your ligand atoms in the Document view—in the example, this is the TDG molecule—and set them in the app using the Set button. All other atoms will be treated as protein by default. Confirm that the app reports the correct number of ligand atoms afterward.
Assign ARAP Atoms Thoughtfully
The ART-RRT method utilizes As-Rigid-As-Possible (ARAP) modeling to simulate ligand motion. This requires defining key ligand atoms as either active (main drivers of motion) or passive, and selecting some protein atoms as fixed to prevent drifts.
- Select an atom like
S1(in the tutorial example) for the active ARAP ligand atom. - Choose a structurally stable protein atom (e.g., CA from HIS 205) as a fixed point.
This careful labeling avoids over-flexible or chaotic motion when the simulation runs, keeping results interpretable.
Visual Feedback Helps
Once the setup is complete, the app visually distinguishes atoms in the viewport: blue for passive ARAP atoms, green for active ARAP atoms, and red for fixed atoms. This immediate feedback lets you double-check your selections before proceeding.
Pro Tip: Coordinate System Alignment
The active ligand atoms move within a user-defined sampling box, which is aligned to the Cartesian coordinate system. If your protein is not well-oriented, the box may not cover relevant unbinding directions, skewing the search. You can use the Edit > Move selection tools in SAMSON to align the complex, though the tutorial sample is already pre-aligned along the Z-axis, which is convenient.
Summary
Paying attention during system setup—especially selecting correct ligand atoms, and wisely choosing active and fixed atoms—saves time and produces much better results. Before running simulations, use the visual aids and setup feedback built into the Ligand Path Finder app to ensure everything is correctly initialized.
Learn more in the full documentation at SAMSON Ligand Path Finder Tutorial.
SAMSON and all SAMSON Extensions are free for non-commercial use. Try it today at https://www.samson-connect.net.