For molecular modelers working with protein-ligand complexes, Nuclear Magnetic Resonance (NMR) remains a go-to experimental method when X-ray crystallography becomes impractical. However, interpreting NMR data in silico, especially ambiguous NOESY peaks involving unassigned methyls, can quickly turn computationally expensive. When using SAMSON’s NMR2 extension, facing this bottleneck is common — and preventable.
If you’re finding that NMR-based structure predictions are taking longer than expected, chances are you’re dealing with too many ambiguous methyl-residue assignments. Fortunately, there’s a simple way to streamline your calculations: methyl pre-assignment.
Why Pre-Assign Methyl Groups?
NMR2 uses a combinatorial search strategy to explore different ways of assigning methyl groups to residues, scoring each based on how well they satisfy observed distance restraints. But the more methyl groups involved, the more combinations to test — and time balloons fast.
By assigning even a single methyl group manually, you’re helping NMR2 rule out incompatible configurations, reducing the search space and speeding up the workflow considerably.
Here’s an example straight from the NMR2 tutorial. Suppose you already know that methyl group M5 corresponds to pseudo-atom QE on residue 130 — information that could come from complementary NMR experiments or the literature.
Then all you need to do is enter:
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M5 = 130 QE |
in the Assigned methyls box within the NMR2 interface:
This simple instruction tells NMR2 not to consider alternative mappings for M5, freeing it to focus computational effort elsewhere.
How Much Work Can You Save?
While the exact time saved depends on how many methyls are involved and how many you assign, even partial assignment like this can drastically reduce the number of configurations. In cases involving more than five methyl groups, preassignment can cut down job times from hours to mere minutes.
It’s a pragmatic tactic, especially if you’re iterating rapidly through docking workflows, comparing binding poses, or preparing structures for simulation ensembles.
What If You Have Incomplete Info?
Even if you don’t have full assignments, NMR2 supports partial assignments. For instance, you can specify:
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same_res = M1 M2 |
to indicate that two methyls belong to the same residue, without locking down which one exactly. But when solid information is available, full assignment is the most impactful and accurate option.
Follow the Tutorial
This tip is part of a broader tutorial on using NMR2 within SAMSON for predicting protein-ligand complexes from NOESY distance restraints. To learn more about setting up the system, preparing restraints, and launching calculations, visit the original tutorial:
NMR2 in SAMSON – Full Tutorial
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON here.