How to Configure Ligand and Protein States for Pathway Exploration

For molecular modelers aiming to discover ligand unbinding pathways from proteins, preparing the system is an essential and sometimes challenging task. A common hurdle lies in defining the starting conformation, selecting ligand and protein atoms correctly, and ensuring proper alignment for accurate simulation. This guide will walk you through these steps using SAMSON’s Ligand Path Finder app.

Step 1: Load the Input Model

Begin by loading the sample system for practice purposes:

  1. Click Home > Download in SAMSON.
  2. Paste this link into the download window: https://www.samson-connect.net/documents/b75291cc-8f4d-4119-8aa3-7d547b83818f.
  3. Select Download. The system contains a structural model of Lactose permease and its ligand, Thiodigalactosid (TDG).

Download the sample document

For custom systems, ensure the model is prepared by removing water and ions, adding hydrogens, and performing a structural validation. You can find more details in the Protein Preparation & Validation tutorial.

Step 2: Define the Starting Conformation

The starting conformation is crucial as it acts as the base state for pathway exploration. In the Document view, locate and select the conformation bound_minimized. Then, in the Ligand Path Finder app, click Set to designate it as the starting conformation. Ensure your system is aligned along the Cartesian coordinates to make the sampling domain efficient.

Set starting conformation

Step 3: Define the Ligand

Next, specify the ligand atoms. In the Document view, locate TDG to select all ligand atoms automatically. Now, click Set within the app to assign these atoms as ligand components. The remaining atoms will default to the protein.

Set ligand atoms

To confirm, check the Advanced information box for a log message such as “31 atoms set as ligand atoms.”

Step 4: Assign ARAP Atom Types

Designate active and fixed atoms for smoother pathway exploration:

  • Active ARAP atoms: These drive the ligand motion. Select the sulfur atom S1 from TDG (conveniently grouped as S1 from TDG in the Document view) and click Add. Passive atoms will then follow the active ones.
  • Fixed ARAP atoms: To anchor the protein, choose a stable atom such as the CA atom in the backbone of HIS 205. This group is named CA from HIS 205. Add it as a fixed ARAP atom by selecting it and clicking Add.

Set fixed atoms

These choices will ensure your system remains stable and focused during simulations.

Final Steps

Once you’ve finished setting up, review your selections using the Select buttons. If needed, adjust the setup by resetting specific parts.

With these foundational steps completed, you’re ready to define the sampling box, configure search parameters, and begin exploring pathways! Refer to the full tutorial via SAMSON's Ligand Path Finder documentation for detailed guidance on running the planner and analyzing results.

Note: SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at SAMSON Connect.

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