When exploring ligand unbinding pathways from proteins, molecular modelers often find themselves struggling with a deceptively simple question: which atoms should I select as the ligand, the active motion drivers, or the fixed anchors? The outcome of your unbinding simulations depends heavily on these choices, yet it’s easy to miss their importance.
In this article, we’ll walk through the process of defining the ligand, active ARAP atoms, and fixed protein atoms using the Ligand Path Finder app in SAMSON. Getting this setup right is key to generating meaningful unbinding pathways and gaining real insights into molecular behavior.
Why Atom Selection Matters
In the ART-RRT algorithm implemented in the Ligand Path Finder, atoms are divided into roles:
- Ligand atoms: These are the atoms of the small molecule (ligand) you’re tracking as it unbinds.
- Active ARAP atoms: A subset of ligand atoms that actively guide the motion during pathway exploration.
- Fixed ARAP atoms: Protein atoms that should remain stationary to prevent global drift during simulations.
Mislabeling or overlooking these roles can lead to paths that are physically meaningless or chemically irrelevant.
Defining the Ligand
Start by selecting the ligand in the Document view. In the tutorial example, the ligand is TDG (Thiodigalactosid):
After selecting the ligand, click the Set button in the app to define the selected atoms as ligand atoms. This tells Ligand Path Finder that the unbinding motion will be based on the movement of these atoms.
Choosing Active ARAP Atoms
The active ARAP atoms direct the ligand’s movement. Choosing too many can slow down computations; choosing poorly can lead to a loss of control over meaningful motion. In the tutorial, the sulfur atom S1 in TDG is used. A predefined group, S1 from TDG, is available in the Document view to simplify selection:
After selecting it, press the Add button in the Ligand Path Finder to define this atom as the active ARAP atom:
Choosing Fixed ARAP Atoms in the Protein
To avoid global movements or distortions of the protein, anchor one or more atoms in known stable regions. The tutorial uses CA from the backbone of HIS 205. Again, a convenient group named CA from HIS 205 is available:
Click Add in the app to register this atom as fixed:
Verifying Your Setup
Once selections are complete, use the Select buttons to review them, or reset mistaken selections using the Reset button:
This verification step ensures your planned simulation has a sound chemical foundation, and that pathway predictions are credible.
Final Thoughts
Thoughtful selection of ligand and ARAP atoms enables more robust and realistic pathway searches using ART-RRT. Whether you’re modeling drug release or probing molecular escape routes, this setup underpins the entire exploration process.
To gain more insights about ART-RRT and ligand unbinding simulations, see the full tutorial at the Ligand Path Finder documentation page.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON at https://www.samson-connect.net.