Struggling with False Positives in Protein Docking? Restrict Your Search Domain

Protein-protein docking can be challenging. One common frustration for molecular modelers stems from the abundance of false-positive predictions—docking orientations that score well but are biologically implausible. These often result from exploring a search space that’s too broad. Fortunately, the Hex Extension in SAMSON offers a streamlined way to narrow search domains for more focused and efficient docking.

This blog post walks you through a particularly useful feature in the Hex Extension: defining range angles to restrict the docking search domain. Understanding how to use this feature can accelerate your search and improve docking results—especially when you already have insights about the binding site.

Why restrict the search domain?

In many docking scenarios, users already have some idea of where the binding site might be. Hex allows you to limit the angular freedom around the intermolecular axis between the receptor and ligand, drastically reducing the number of sampled orientations. This means:

  • Shorter search times
  • Fewer irrelevant poses
  • Improved quality of retained solutions

Let’s walk you through the process.

Step-by-step: Setting up range angles in SAMSON

  1. First, open the Hex app in SAMSON: Home > Apps > Biology > Hex.
  2. Select your receptor and ligand in the document view. In the tutorial example, 2PTC_E is the receptor and 2PTC_I is the ligand.
  3. Set the Sampling method to Range angles.
  4. Click Advanced parameters in the Hex GUI to open the angular settings (see below).

Advanced parameters of Hex

  1. Adjust the Range angles for both the receptor and ligand. For instance, try setting both to 45 degrees.

This defines a spherical cone around the intermolecular axis, limiting the orientations sampled during docking. To visualize this, Hex displays the cones in the molecular scene, as shown below:

Angle ranges

Best practices and tips

  • Pre-orient the ligand: If you know the approximate binding region, manually move the ligand into a favorable orientation before restricting angle ranges. This helps ensure the search is focused around the actual binding interface.
  • Avoid over-restricting: Start with moderately narrow angles (e.g., 45 degrees) and experiment. Going too narrow too early might miss valid poses.
  • Use visual aids: Toggle visual models like ribbons or Gaussian surfaces through Visualization > Visual model to better understand molecule orientation.

When to use this approach?

Narrowing your search range is especially beneficial when:

  • You’re docking homologous proteins with known interfaces.
  • You’ve already validated the approximate location of the binding site through other tools or literature.
  • You’re aiming for time-efficient screening of multiple parameter configurations.

Reducing the search domain not only saves time but also increases the interpretability of your results—something most modelers are always looking for.

Want to explore this functionality step-by-step? Visit the complete Hex Extension tutorial for more details.

SAMSON and all SAMSON Extensions are free for non-commercial use. Download SAMSON at https://www.samson-connect.net.

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