When modeling ligand unbinding from a protein, one common challenge is evaluating energies and relaxations during the simulation. To get meaningful results, you first need a proper setup of the energy model and a reliable method for system relaxation during sampling.
The Ligand Path Finder app in SAMSON lets you explore possible unbinding pathways using ART-RRT (As-Rigid-As-Possible Rapidly-exploring Random Tree). One key step is setting up an appropriate interaction model and state updater. This configuration directly influences how pathway energies are estimated and how the system adapts to changes in the ligand conformation.
Why this setup matters 🧪
Without reliable energy evaluations, ligand paths can be physically irrelevant. That’s why the Ligand Path Finder tutorial recommends using:
- Universal Force Field (UFF) as the interaction model
- FIRE (Fast Inertial Relaxation Engine) as the state updater
UFF is a general-purpose force field that works across a wide range of molecules, making it suitable for protein-ligand systems. FIRE efficiently minimizes the system after each sample step, helping it to relax and stay close to realistic conformations.
How to configure this in SAMSON
In the Ligand Path Finder app, go to the Settings tab. There, you’ll need to make two selections:
- For Interaction Model, choose Universal Force Field (UFF) from the dropdown menu.
- For State Updater, select FIRE.
If you don’t see the FIRE option, make sure the extension is installed (you can find it on SAMSON Connect).
Fine-tuning FIRE settings
Once selected, a pop-up will ask whether you want to apply a new model. Click Yes. Next, the UFF setup window will appear—choose to use existing chemical bonds when prompted.
Two parameter windows will appear:
- Universal Force Field – Displays system energies
- FIRE Properties – Lets you configure how the state is updated
Set the FIRE updater like this:
- Step size: 1 femtosecond (fs)
- Number of steps: 1
These settings ensure that every sampled ligand motion is quickly followed by a lightweight relaxation. This prevents geometry artifacts and maintains consistency in energy assessment throughout the simulation.
Final thoughts
Time invested in properly configuring your interaction models pays off through more meaningful and reproducible results. Whether you’re screening ligand exit paths or setting the stage for enhanced sampling methods like P-NEB, getting the energy setup right is essential.
You can explore the full tutorial and additional options in the official documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON at https://www.samson-connect.net.