Avoid Ligand Confusion: Correctly Selecting Ligand Atoms in Ligand Path Finder

One of the most common setup issues encountered by molecular modelers working on protein-ligand interactions is an incorrect definition of the ligand itself. This can lead to inaccurate path predictions, unexpected energies, and even failure of the algorithm to find a path at all.

If you’re using the Ligand Path Finder app in SAMSON to explore possible unbinding pathways, you’ll need to define the ligand atoms explicitly. In this post, we’ll show you how to do it properly — and why it matters.

When the Ligand Isn’t Defined Correctly

Ligand Path Finder uses a combination of T-RRT planning and ARAP modeling to explore possible exit routes of a ligand from the protein’s binding site. It treats everything outside the selected ligand as protein — meaning that if your ligand selection is wrong or incomplete, the method will try to move the wrong atoms, resulting in misleading trajectories or failed simulations.

How to Select the Right Ligand Atoms

In the provided tutorial, the ligand is Thiodigalactosid (TDG), and the selection is done directly in the Document view. Here’s the process:

  1. Locate TDG under the molecular structure in the Document view.
  2. Click on TDG to select all ligand atoms. Make sure nothing outside of TDG is selected — no protein residues, solvent atoms, ions, or alternate conformations.
  3. In the Ligand Path Finder app, click the Set button in the “Define the ligand atoms” section. This will tell the app what to treat as the ligand.

Set ligand

A confirmation will appear stating how many atoms have been set as ligand atoms. In the tutorial example: “31 atoms set as ligand atoms”.

Why This Step is Critical

If the ligand atoms are not specified correctly, the active and passive ARAP motion will target the wrong subset of the system. This can lead to energy evaluations that do not reflect the actual behavior of the ligand, and the resulting trajectories may be unphysical.

Correct atom selection also ensures smoother downstream steps, like defining active atoms for ARAP modeling and calculating minimized conformations.

Tips for Smooth Selection

  • Use the Document view or Viewport with the Selection Editor to pick atoms manually.
  • For large or multi-fragment ligands, verify all parts are included.
  • Group helper objects (like “TDG” and “S1 from TDG”) in your model to make selection easier.

Remember that only the atoms explicitly marked as ligand will be considered movable by the planner.

Once the Ligand Is Set

After setting the ligand atoms, you’re ready to define active and fixed atoms for ARAP, the sampling space for the motion, and initiate the pathway planning. All subsequent stages depend on this initial definition being correct.

This simple step — often overlooked — can determine whether your ligand escape analysis is meaningful or not.

To learn more and follow the full tutorial, visit the Ligand Path Finder documentation.

SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON from https://www.samson-connect.net.

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