A Practical Way to Improve Ligand Unbinding Simulations with P-NEB

When simulating molecular transitions, one of the most common challenges is identifying realistic paths between two conformations of a system—especially in cases like ligand unbinding from a protein. Often, modelers generate intermediate structures manually or via linear interpolation, but these may not reflect physically plausible pathways. This is where the Parallel Nudged Elastic Band (P-NEB) method in SAMSON comes in handy.

P-NEB allows you to refine a transition path using energy-based optimization to identify a pathway that minimizes potential energy across structure conformations. It’s not a replacement for molecular dynamics, but a valuable complement—especially when dynamics is too slow or computationally expensive to explore transitions at relevant timescales.

Why Use Paths Instead of Conformations?

Imagine you have generated a dozen conformations of a ligand moving away from a pocket in a protein. You could directly apply P-NEB to this conformation set, but that usually takes more time. Instead, you can create a path consisting of the same snapshots and apply P-NEB directly to that. Paths utilize internal structure for spacing and sampling, making the process quicker and often more stable.

Tip

You can combine conformations into a path directly in SAMSON: select them in the Document View, then right-click and choose Conformation > Create path from conformations.

Getting Started with Path Optimization Using P-NEB

Once your path is ready, optimizing it with P-NEB is straightforward:

  1. Load a sample document from the Home > Download menu. For instance, try this ligand unbinding example: Zinc unbinding path.
  2. Open the P-NEB App from Home > Apps > All > P-NEB.
  3. Select the path node you want to refine in the Document View.
  4. Configure P-NEB options:
    • Spring constant: 1.00
    • Loops: 100
    • Interaction model: Universal Force Field
    • Optimizer: FIRE
    • Parallel execution: Checked
    • Climbing image: Unchecked (for now)
    • Suffix name: NEB
  5. Click Run.

You’ll be prompted about handling existing bonds—accept the default to use them. The computation begins, and you can follow the progress in the status bar.

P-NEB computation progress

Once it’s complete, the refined path appears in the Document View. This updated trajectory better captures realistic intermediate conformations along the unbinding path.

Resulting path

Inspect and Replay the Optimized Path

Double-clicking the new path in the Document View animates the path. You can also examine specific frames with the Inspector or access context options with a right-click. This helps you visualize the trajectory and understand where key state transitions happen.

A Simpler Workflow for Complex Transitions

For complex systems like protein-ligand interactions, having this in-between tool for path refinement can bridge the gap between rigid conformer interpolation and full MD. It’s faster, stable, and useful when you want clarity on how a molecule might escape a binding pocket—or rearrange itself between stable states.

To learn more and experiment with P-NEB in your own projects, check out the full tutorial: Optimize transition paths with the Parallel Nudged Elastic Band method.

SAMSON and all SAMSON Extensions are free for non-commercial use. You can download the platform at https://www.samson-connect.net.

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