One of the recurring challenges in molecular modeling is understanding how a biomolecule—often a protein—transitions from one structure to another. Whether you’re studying loop movements that expose a binding pocket, domain shifts, or global conformational changes, capturing and controlling such structural transitions is no trivial task.
SAMSON’s Normal Modes Advanced Extension offers a practical way to address this challenge. If you’ve ever faced the problem of simulating a motion to reach a known functional conformation—say, an open state of a receptor—this tool can help demystify that transition. Let’s take a closer look at how you can define a target structure and find the best combination of nonlinear normal modes that transform one conformation into another.
The Pain: Simulating Transitions Between Known States
Imagine you’ve crystallized a protein in its inactive (closed) state, but your real interest lies in its active (open) form. You want to generate the intermediate steps or simulate a plausible pathway from one to the other. Conventional molecular dynamics might be too slow or resource-intensive for this purpose.
The Normal Modes Advanced module offers a quicker route. By analyzing nonlinear normal modes, it lets you determine motion directions intrinsic to the structure’s geometry and potential. What’s more, you can combine these modes to drive the structure toward a user-defined shape. This is exactly what the Structure Definition tab enables you to do!
Defining Pockets and Targets
First, in the Structure Definition tab, you can manually select atoms or residues that constitute a pocket or a flexible domain of interest. These selections define the part of the structure you want to open, close, or otherwise manipulate.
Then, you can specify a target conformation. This can be another experimentally determined state or a hypothesized arrangement of residues and atoms. The software will compute the optimal combination of normal modes to transform the current structure toward the target, while preserving molecular integrity.
Visualizing the Trajectory
Once the optimal combination is identified, SAMSON allows you to visualize how the structure moves along the computed pathway. This isn’t just useful for visual storytelling—it’s a way to understand mechanism. For example, if a gating loop opens only when a domain rotates in a certain direction, the animation will reveal that coupling.
Why This Matters
Too often, conformational changes remain abstract ideas in the literature—”the structure opens,” “the pocket closes,”—without mechanistic insight. With the Structure Definition feature in the Normal Modes Advanced module, you can test such hypotheses and generate trajectories that bridge known experimental states.
This is particularly useful for those working in areas like:
- Drug design, where pocket accessibility affects ligand binding
- Enzyme engineering, where loop motion controls catalysis
- Structural biology, where conformational heterogeneity is central
Rather than just looking at static before-and-after snapshots, this feature helps you explore the dynamic ‘between’—what many modelers crave but struggle to estimate with conventional tools.
To learn more about how to use the Structure Definition tab and nonlinear normal modes in SAMSON, visit the full tutorial at https://documentation.samson-connect.net/tutorials/nma/calculating-non-linear-normal-modes/.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.