Before running advanced analyses such as ligand unbinding pathway searches or energy minimizations, it’s critical to properly prepare your molecular models. For many molecular modelers, skipping this step—or not doing it thoroughly—leads to frustrating errors during simulation, non-physical results, or wasted computation time.
In SAMSON, preparing your system is straightforward but essential. This includes removing alternate locations, deleting unnecessary water and ions, and adding hydrogens. These basic steps act like a foundation: invisible when everything works well, but the cause of problems when overlooked.
When Should You Prepare Your Model?
You should always prepare your model before minimizing its energy or launching any dynamic or pathway-based simulation. Even PDB files from trusted sources can contain structural quirks or ambiguities—such as partial occupancies—that may interfere with computations in SAMSON.
For example, when working with the Ligand Path Finder app in SAMSON, a poorly prepared protein-ligand complex may cause minimization issues or strange ligand movements that make interpretation difficult. A few minutes of preparation can save several hours of debugging.
How to Prepare Your Protein-Ligand System
To access the preparation tools in SAMSON, follow these steps:
- Navigate to Home > Prepare.
- Use the protein preparation tool to clean your structure: remove alternate locations, water molecules, and ions.
- Add hydrogens to complete the structure and ensure realistic interactions.
This will make your molecules compatible with downstream processes such as force field calculations or ligand path search algorithms.
Note
If you’re working with your own structure (not the prepared tutorial example), thorough preparation and alignment are even more important. SAMSON provides rotation and alignment tools to help you align the system along the desired Cartesian axis, which is crucial for defining sampling boxes effectively.
Once your model is prepared, you can use the Ligand Path Finder app to start exploring possible unbinding pathways in a physically consistent environment.
How to Fix Common Preparation Issues
Sometimes a model might need additional adjustments. If backbone atoms are missing or if bond orders aren’t properly inferred, you can use the context menu in SAMSON to apply fixes or reassign atom types. For ambiguous regions (e.g., loop regions or flexible side chains), consider rebuilding or replacing them using dedicated tools or fragment libraries.
Proper model preparation is especially important when restraints, such as fixed atoms or sampling boxes, are applied—since incorrect spatial configurations can lead to misleading trajectory results or fail to find realistic unbinding paths.
In short, setting up the system correctly doesn’t just help—it’s essential to avoid misleading outcomes and make the most of SAMSON’s powerful simulation tools.
To dig deeper into model setup—including visual inspection and alignment—visit the full Ligand Path Finder tutorial page here.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.