One common challenge in computational molecular design is correctly preparing a protein-ligand system for dynamic simulations. Poor initial setup can lead to unusable results or misleading data, especially when exploring ligand unbinding pathways. In this post, we focus on a frequent pain point: setting up the ligand and its associated atoms before generating unbinding trajectories.
If you’re using the Ligand Path Finder app in SAMSON, proper system setup is essential for obtaining accurate unbinding paths. Three types of atoms must be clearly defined: the ligand atoms (to be unbound), the active ARAP atoms (guide points for motion), and the fixed protein atoms (to avoid protein drift).
Step 1: Selecting the Ligand
In the Document view, locate your ligand — in the tutorial example, it’s TDG (Thiodigalactosid). Click on it to select all the ligand atoms, then use the Set button within the Ligand Path Finder app. This step distinguishes the ligand from the rest of the protein, preparing it for path calculations.
Step 2: Defining Active ARAP Atoms
Active ARAP atoms are used as control points for ligand motion. You typically want to select atoms that represent the core or handle of your ligand. In the TDG example, the sulfur atom S1 is chosen. In the Document view, this atom is conveniently grouped under S1 from TDG. Double-click the group to select it, then hit Add in the app to mark it as active.
Step 3: Defining Fixed Atoms in the Protein
To ensure the protein remains relatively stationary during the simulation, you’ll need to fix specific atoms. These are atoms that are assumed to be static and should not follow the ligand. For example, the backbone CA atom in the HIS 205 residue is used. In the sample, this atom is grouped under CA from HIS 205. Select it and click Add to fix it in place.
Quick Tips
- You can double-check your selections using the Select buttons to ensure everything is correctly assigned.
- If you make a mistake, each assignment can be removed using its corresponding Reset button.
- Colored atoms in the viewport help visualize your setup: red for fixed atoms, green for active, and blue for passive.
Properly defining ligand and ARAP atoms ensures better pathway prediction and minimizes noise in your simulation. Taking a few extra minutes to get this right can save a lot of time in post-processing and interpretation.
To learn more, read the full tutorial on setting up your system in the Ligand Path Finder documentation: Ligand Path Finder Documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON and explore molecular modeling features at samson-connect.net.