When working with complex protein-ligand systems in solution, one of the biggest bottlenecks in using Nuclear Magnetic Resonance (NMR) data—especially for integrative modeling—is the time it can take for structure prediction tools to evaluate all possible methyl group combinations. If you’ve used NMR-derived distance restraints before, you’re probably familiar with this computational challenge, especially when dealing with many unassigned methyl peaks.
Fortunately, when using the NMR2 extension within SAMSON, there’s a simple yet powerful trick: you can assign known methyls to help the algorithm prune the search space efficiently. Let’s look at how this works and why you might want to use it.
What’s the problem, exactly?
NMR2 searches for combinations of methyl assignments that best satisfy a set of distance restraints derived from NMR experiments (such as NOESY). This process can run into a combinatorial explosion as the number of unassigned methyls increases, which slows down calculations and can delay insights into ligand binding modes.
However, if you’ve nailed down some assignments through separate NMR experiments or expert analysis, you can feed those assignments into NMR2 and significantly cut down on computation time.
How to use assigned methyls in NMR2
After setting up your protein, ligand, and binding site in SAMSON’s Document view and the NMR2 interface, navigate to the Assigned methyls box within the interface. Here, you can specify known methyl identities using the following format:
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M5 = 130 QE |
This tells NMR2 that M5 corresponds to the pseudo-atom QE on residue 130. NMR2 will then lock in that assignment and only search over the remaining methyl assignments, improving performance and potentially boosting prediction accuracy for the rest of the unassigned groups.
Here’s the interface where this goes:
It’s particularly useful in cases where you have sparse experimental data or when you’re working with highly symmetric systems where many groups are chemically equivalent but spatially distinct.
What about partial knowledge?
What if you don’t have full methyl assignments but partial ideas (e.g., two methyls are on the same residue)? You can enter this in the Partial assignment box using the same_res keyword:
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same_res = M1 M2 |
…or restrict possible residues types:
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M1 = MET ILE |
Partial assignments don’t lock down configurations, but guide the algorithm towards more probable search spaces.
Why it matters
By taking a few extra minutes to incorporate known or partially known assignments, you can drastically reduce runtime and increase the interpretability of your protein-ligand prediction. For iterative modeling workflows, being able to test hypotheses or new compounds faster without overburdening computational resources can be a big win.
Learn more
You can learn about the full workflow of predicting protein-ligand complexes using NMR2 inside SAMSON by visiting the complete tutorial: https://documentation.samson-connect.net/tutorials/nmr2/predicting-protein-ligand-complexes-using-nmr2/
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.