Defining a realistic energy environment is essential when simulating molecular events such as ligand unbinding. Without the appropriate setup, computed pathways may be energetically unreliable or misleading. Fortunately, the Ligand Path Finder app in SAMSON provides a streamlined process to set this up—if you know where to start.
In this post, we’ll walk through the process of setting up energy models critical for pathway generation. Specifically, we’ll look at how to assign an interaction model and a state updater. This is particularly useful for molecular modelers performing pathway exploration who want to ensure that energetic continuity and relaxation steps are appropriately taken into account.
Choosing the Right Interaction Model
Before generating ligand unbinding paths, it’s important that the energy evaluation reflects realistic molecular interactions. In SAMSON’s Ligand Path Finder app, this is done via the Settings tab where you assign an interaction model and a state updater.
To begin, select Universal Force Field (UFF) as your interaction model. UFF is broadly compatible with organic and inorganic molecules, making it a reliable choice when working with ligand-protein complexes.
After selecting UFF, a dialog box will appear asking whether to use existing bonds. It’s generally best to use existing bonds to maintain chemical consistency with your model.
Adding the FIRE State Updater
After selecting UFF, choose the FIRE (Fast Inertial Relaxation Engine) state updater. This updater minimizes energy via inertial dampening and is well-suited for structural relaxation during path sampling.
If you don’t see FIRE listed, make sure it’s installed from SAMSON Connect. You can double-check your setup against the requirements section of the original tutorial.
Fine-Tuning Minimization Parameters
Once selected, both the UFF and FIRE windows will open. At this stage, adjusting the FIRE parameters ensures smoother pathway construction. The recommended settings from the tutorial provide a good starting point:
- Step size: Set to 1 fs
- Number of steps: Set to 1 per sampling iteration
These values balance computational efficiency with structural accuracy. With every sampled conformation, a quick energy minimization step ensures the system remains close to a physically meaningful configuration.
Why This Matters
Setting up the interaction model and state updater isn’t just a technical detail—it’s a critical step that affects the outcome. Poorly relaxed structures can generate spurious energy barriers or artificial pathway artifacts. By ensuring that both UFF and FIRE are properly configured, users can build a reliable foundation for accurate simulations.
For users unfamiliar with force fields or energy minimization schemes, the combination of UFF and FIRE offers a practical default. And because the parameters are visible and customizable, advanced users can adapt them to specific molecular systems and constraints.
Once your energy model is in place, you’ll be ready to move forward with the remaining setup: defining active atoms, ligands, fixed residues, and launching your path-finding simulations with greater confidence and reproducibility.
Learn more about setting up ligand unbinding simulations in the official documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.