Loop Modeling

The goal of loop modeling is to predict the conformation of a relatively short stretch of protein backbone and sidechain. As one example, it's not uncommon for crystal structures to be missing density in some regions. Loop modeling can be used to predict structures for these regions. As another, homology models often need to account for short insertions or deletions. Loop modeling can be used to predict how these sequence changes affect structure.

Loop modeling in Rosetta is very configurable, but the basic algorithm goes like this:

  • Inputs:

    The inputs are a protein structure and a set of indices specifying where one or more regions to model (i.e. the loop or loops) start and stop.

  • Step 1: Initial build

    The algorithm starts by building an initial backbone for each loop being sampled. This backbone is just a starting point for the rest of the algorithm, so it's only realistic in the sense of having reasonable bond lengths and not completely clashing with anything. Note that by skipping this step, you can use the loop modeling algorithm for ensemble generation.

  • Step 2: Centroid refinement

    The algorithm continues by refining the loop conformation in the context of the centroid score function. The centroid score function represents the backbone atoms in full detail, but abstracts the sidechains into spherical blobs. This creates a smoother energy landscape that is easier to explore broadly. The landscape is sampled using Monte Carlo "local backbone moves", i.e. moves that perturb the backbone within the region being sampled but not outside of it.

  • Step 3: Fullatom refinement

    The algorithm finishes by refining the loop conformation in the context of the fullatom score function. This is conceptually very similar to the centroid refinement discussed above, except now all the atoms are represented in full detail and both sidechain and local backbone Monte Carlo moves are employed.

  • Outputs:

    Each loop modeling simulation takes about 30 minutes and produces one model structure as output. Typically, to predict a structure for a single loop, you would generate at least 500 such models and take whichever has the lowest energy. You might also calculate an RMSD for each model relative to the lowest scoring one and look for funnels in score vs. RMSD space.

Relevant movers

See Also