Finding ligand unbinding pathways can be complex, especially when accurate energy evaluations are essential to guide the search. If you’re using SAMSON’s Ligand Path Finder, correct setup of the energy model is a critical early step. In this post, we’ll walk through the process of configuring the interaction and state updater models — specifically choosing the Universal Force Field (UFF) and connecting it with the FIRE (Fast Inertial Relaxation Engine) state updater. These are key ingredients in calculating energies during ligand motion simulations.
This setup is important because the Ligand Path Finder relies heavily on energy minimizations to ensure realistic motion simulations. Whether you’re modeling drug unbinding mechanisms or exploring exit tunnels, poor starting conditions will lead to unrealistic results — or no result at all.
Step 1: Make Sure Your System is Minimally Prepared
Before you begin energy model setup, the system should already be minimized. If needed, use the Edit > Minimize function in SAMSON, which applies UFF and takes care of initial relaxation. You can refer to the minimization guide if you’re unsure how to do this.
Step 2: Choose an Interaction Model and State Updater
With your Ligand Path Finder app open, go to the Settings tab. You’ll find an area labeled “Define interaction and state updater models”. From the dropdown menus, select:
- Interaction model: Universal Force Field (UFF)
- State updater: FIRE
These define how the system’s energies and dynamics are computed. If FIRE isn’t listed, first ensure it’s installed via the SAMSON Connect Extension Store. You can find it at this link.
Step 3: Confirm Parameter Setups
Once you activate UFF and FIRE, two new property windows will appear, showing energy values and editable parameters.
In the FIRE Properties window, adjust:
- Step size:
1 fs - Number of steps:
1
These defaults are lightweight and allow for fast, iterative motion sampling. You can fine-tune these later depending on convergence or accuracy needs.
During UFF setup, you’ll be prompted whether to use existing bonds. Be sure to select “use existing bonds” to preserve the integrity of your starting model.
Why Does This Matter?
Correctly configuring the energy model enables the Ligand Path Finder to judge whether any trial motion is physically feasible. The combination of UFF (for evaluating molecular interactions) and the FIRE updater (for minimization) ensures the geometry of your molecule remains chemically valid during motion sampling.
This setup forms the basis for the core exploration, helping you detect realistic exit pathways and minimizing artifacts caused by overly rigid or under-constrained systems.
Learn More
This post only covers the energy model setup step of the Ligand Path Finder workflow. To continue with defining the ligand, sampling box, or executing the planner, visit the full tutorial on the official documentation page: Ligand Path Finder Documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.