When studying ligand unbinding in molecular systems, simply knowing the start and end states is often not enough. The path a ligand takes while moving from its bound state to an unbound state can provide useful insights into binding site accessibility, energy barriers, and potential allosteric effects. But generating this unbinding trajectory with high accuracy can be challenging. Ligand pathways obtained from methods like interpolation often contain high-energy artifacts or non-physical motions, making them unreliable for further analysis or simulation.
This is where the P-NEB (Parallel Nudged Elastic Band) app in SAMSON can help. It provides a way to optimize transition paths to produce smooth, physically meaningful trajectories that pass through minimum-energy regions. In this blog post, we’ll show how to use P-NEB to refine ligand unbinding paths, starting from a trajectory obtained with the Ligand Path Finder extension or any other tool you’re using to guess a path.
Why optimize unbinding paths?
Imagine trying to estimate how a ligand moves based only on visual guesses or basic linear interpolation. Without optimization, you might end up with a transition path that jumps unrealistically through high-energy atomic clashes or overlooks energetically favorable shortcuts.
By applying the P-NEB method, you can:
- Refine the guessed path between bound and unbound states
- Reveal energy barriers and saddle points in the process
- Improve input trajectories for downstream free energy calculations
Step-by-step: Applying P-NEB to a path
Assume that you already have a guessed transition path displayed as a SAMSON path node. Here’s how to improve it with P-NEB:
- Open the P-NEB App from
Home > Apps > All. - In the Document View, select the path you want to optimize.
- Adjust the following settings in the P-NEB App interface:
- Spring constant:
1.00 - Number of loops:
100 - Interaction model:
Universal Force Field - Optimizer:
FIRE - Parallel execution: check this box to enable parallelization
- Suffix name:
NEB
- Spring constant:
- Click Run and confirm the use of existing bonds in the UFF setup window.
Computation will start and the status bar will show progress.
Once complete, a new optimized path will appear in the Document View with the chosen suffix (e.g., NEB). You can double-click to play the animation or select the new path to inspect it in more detail.
How good is your refinement?
The computation summary in the P-NEB interface shows how the energy profile evolved. You can now examine a physically meaningful, smooth unbinding path. It becomes much easier to spot potential bottlenecks or energy barriers, especially helpful when analyzing rare events or planning umbrella sampling windows.
A tip: prefer paths over conformations
You can also apply P-NEB to a set of conformations. But if your system is large or the sequence is long, creating a path first is usually more efficient. Just right-click your selected conformations and choose Conformation > Create path from conformations.
Refining transition paths doesn’t need to be a black box or trial-and-error. With P-NEB in SAMSON, you can turn a guessed trajectory into an optimized path based on molecular mechanics — without ever leaving the user interface.
Want to explore more? You can follow the full tutorial here.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON from https://www.samson-connect.net.