One of the recurring challenges in computational structural biology is understanding and predicting how biomolecules open or close around functional sites, such as ligand-binding pockets. Experimental structures often show only a few static snapshots—yet the biological activity is tightly linked to dynamic transitions between conformational states.
Have you ever found yourself wondering which motions in a protein enable the opening of a buried binding site, or how to model transitions between open and closed states? If so, the Structure Definition feature of the Normal Modes Advanced extension in SAMSON may help guide your exploration.
Targeted pocket opening, simplified
SAMSON’s Normal Modes Advanced (NMA) module not only calculates nonlinear normal modes (NNM) efficiently—it also allows you to define structural pockets or target conformations, and then automatically computes the best combination of normal modes that deforms your structure to achieve that motion.
This is especially useful when you already have a known closed conformation and you suspect that binding may require pronounced loop or domain motions. Or when you’ve docked a ligand that requires the protein to be more open—but you’re not sure which internal degrees of freedom would make that possible.
How it works
- In the Structure Definition tab of the NMA module, select the residues or atoms that define the pocket or region you care about. This could be the entrance to a catalytic site or the interface in a protein-protein complex.
- Optionally, you can also define a target structure that you want to reach—for example, an open conformation derived from another PDB model or from a structural prediction.
- NMA searches for the combination of normal modes that brings your system as close as possible to your defined target structure or causes the opening/closing motion of the setup pocket.
This removes much of the guesswork: rather than manually combining modes and visually inspecting the effects, SAMSON gives you a direct path to functionally relevant conformational sampling.
Applications and benefits
This tool provides a user-friendly solution to a class of problems that typically require considerable expertise or scripting work. Some examples of how scientists could apply this include:
- Simulating the opening of buried allosteric pockets for virtual screening campaigns
- Generating intermediate conformations along a functional pathway
- Comparing modeled trajectories with known open/closed experimental structures
- Improving initial guesses for docking ligands in flexible binding pockets
Visualizing structural transitions
The NMA module visualizes the continuous transformation between states using animations and allows for real-time feedback as you adjust the mode combinations. Check out below how the pocket-targeting workflow plays out in practice:
In this case, the user has selected a target pocket and SAMSON highlights in real-time the deformation corresponding to the best-fit combination of normal modes.
A more advanced option allows you to define a target conformation—either imported or generated—and determine the best deformation from your starting conformation to the desired one:
Conclusion
Whether you’re studying gating mechanisms, searching for hidden cryptic sites, or generating candidate conformers for flexible docking, the ability to target normal modes at specific structural outcomes offers a powerful addition to the molecular modeler’s toolkit.
Learn more in the official documentation: Nonlinear Normal Mode Analysis in SAMSON.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON at https://www.samson-connect.net.