Finding ligand unbinding pathways through protein tunnels is a common need in molecular modeling. But did you know that the way you define the sampling region can significantly influence the results?
In this blog post, we focus on a critical aspect of using the Ligand Path Finder in SAMSON: how to define the sampling box to achieve more biologically meaningful and computationally efficient unbinding paths.
Why the sampling region matters
When using sampling-based planning algorithms like ART-RRT, the search space is constrained within a box surrounding the ligand. This box is where the active atoms of the ligand are allowed to move during the unbinding simulations.
The size and position of this box bias the direction of ligand motion. A box that is too small might clip possible unbinding tunnels. A box that’s too large increases computational cost and introduces irrelevant directions.
Defining the sampling box in SAMSON
In the Ligand Path Finder app, defining the sampling region is done in the “Set the sampling region” section. The app initially suggests a box size that encloses both ligand and protein atoms. However, you can and often should adjust it.
For example, in the provided tutorial, the sampling box is manually adjusted to favor an unbinding direction toward the periplasmic side of the protein structure. This makes sense if that region is biologically plausible for ligand exit.
Recommendations for better results
- 🎯 Align the system: Before defining the box, orient the protein-ligand complex to match the Cartesian axes. This helps you define meaningful box dimensions.
- 🔍 Review biological context: Consider known or likely ligand exit routes based on crystal structures or literature to guide box placement.
- 🛠️ Adjust dynamically: You can tweak box dimensions and rerun small test searches to see how results differ. This is especially helpful to avoid missing exit pathways.
- 📦 Be specific: Narrower boxes might help speed up computation if you already have a hypothesis about the exit path.
A small change that makes a big difference
Many users tend to accept the default sampling box and run into suboptimal or uninterpretable results. By taking a minute to customize this region based on your system’s geometry and hypothesis, you make sure your computational effort is focused on the most productive region in the conformational space.
Want to go beyond this? Check the original full documentation and tutorial for more features and settings available in the Ligand Path Finder: Ligand Path Finder Documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. To get SAMSON, visit https://www.samson-connect.net.