When exploring ligand unbinding mechanisms in protein-ligand systems, one of the most frequent sources of confusion comes from setting up the proper energy evaluation models. If your energy calculations are mismatched or incomplete, it can stop meaningful trajectory generation altogether—or worse, produce misleading results.
This blog post is a practical walkthrough of how to properly configure interaction and state updater models using the Ligand Path Finder app in SAMSON. Getting this part right ensures that your simulations run smoothly and that your results are reliable and reproducible.
Why Does This Matter?
At the heart of methods like ART-RRT, which is used to explore ligand exit pathways, is the need to calculate forces and energies accurately. These methods rely on two key components:
- An interaction model (to assign energy values to molecular conformations)
- A state updater (to update the molecular system during minimization steps)
Improper configuration of either of these can dramatically affect the system’s ability to find realistic unbinding paths. Fortunately, SAMSON makes this setup fairly intuitive—if you know the right steps to follow.
Step-by-Step Setup
Once the Ligand Path Finder app is launched (via Home > Apps > Biology), head to the Settings tab. Here you’ll choose the appropriate interaction and state updater models for your system.
1. Set the Interaction Model
In the dropdown for the interaction model, choose Universal Force Field (UFF). This is a general-purpose force field that works well for a wide range of molecular systems, especially if you’re exploring ligand motion broadly.
2. Set the State Updater
Select FIRE (Fast Inertial Relaxation Engine) as the state updater. If you don’t see FIRE in the list, make sure you’ve installed it by visiting SAMSON Connect.
3. Apply the Models
When prompted to apply the new model, click Yes. The UFF setup will then ask if you want to use existing bonds—choose use existing bonds and confirm.
4. Fine-Tune Parameters
After confirmation, two properties windows will appear:
- UFF Properties: This lets you inspect current energy parameters and make basic adjustments if needed.
- FIRE Properties: Here, you should set:
- Step size:
1 fs - Number of steps:
1
This configuration ensures that each time a new state is sampled during the unbinding simulation, it is accurately minimized before continuing.
A Quick Tip Before You Begin
Make sure your molecular system is already minimized before launching the Ligand Path Finder. You can do this within SAMSON using Edit > Minimize, which applies the UFF minimization automatically.
Note: You can refer to the full documentation on system minimization here: Minimizing Systems.
Conclusion
Correctly setting up your interaction and state updater models is foundational to everything else in ligand pathway discovery. It only takes a couple of minutes, but skipping or misconfiguring this setup can derail an entire investigation. Master these steps, and you’ll save hours of trial-and-error later on.
To learn more about exploring ligand pathways using ART-RRT and other advanced features, read the full tutorial here.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON here.