Tool: Model Loops

Model Loops is an interface to the Modeller program, either installed locally or run on a web service hosted by the UCSF RBVI. The command-line implementation is modeller loops or modeller refine. See also: Modeller Comparative, Rotamers, Build Structure, AlphaFold, Task Manager

Model Loops builds parts of a protein without using a template. Missing segments can be built de novo, or existing segments refined by generating additional possible conformations. Parts that need building or refinement are often loop regions. The protein sequence to be modeled is the target.

Modeller is developed by the Šali Lab, and its users should cite:

Comparative protein modelling by satisfaction of spatial restraints. Šali A, Blundell TL. J Mol Biol. 1993 Dec 5;234(3):779-815.

The following are required for each chain to be modeled:

1. The atomic structure of at least part of the protein, open in ChimeraX.
   
   
2. A sequence that includes the segments to be filled in or refined, open in the Sequence Viewer (as a single sequence or within a multiple sequence alignment) and associated with the protein structure.

   The target sequence can be taken from the structure metadata (and shown for a specific chain using the menu: Tools... Sequence... Show Sequence Viewer), or fetched from UniProt, or opened from a file. The sequence must be the same as the sequence of the structure, except that differences are permitted within the segments to be filled in or refined, as well as any adjacent positions designated as flexible; the residue types shown in the Sequence Viewer will be used to model those segments. Accuracy can be quite high for shorter loops, but falls off rapidly with length (>50% poor predictions for segments with 10+ residues including the flexible positions, see Table 1 in Fiser et al., Protein Sci. 9(9):1753 (2000)).

   Modeling multiple different chains in a complex requires a separate sequence alignment for each unique chain. For example, simultaneously modeling the α and β chains within an α2β2 tetramer requires both α subunits to be associated with one alignment containing the target α sequence, and both β subunits to be associated with another alignment containing the target β sequence. To instead model only one αβ dimer within the tetramer, the other two structure chains should be dissociated from the sequences.

3. A Modeller license key. Academic users can register free of charge to receive a license key. Commercial entities and government research labs, please see Modeller licensing.

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Startup and Input

Model Loops can be opened from the Sequence or Structure Prediction section of the Tools menu and manipulated like other panels (more...). It can also be started from the Sequence Viewer context menu.

One sequence alignment per target should be chosen (highlighted) in the top section of the dialog. Immediately below, for each chosen alignment, the name of the target sequence should be selected from the pull-down menu.

Basic settings:

• Number of models (initial default 5, maximum 1000) – number of models to create
• Model – which parts of the protein sequence to build or refine:
  • all missing structure (initial default) – all missing segments of the structure relative to the associated sequence
  • internal missing structure – all non-terminal missing segments of the structure relative to the associated sequence
  • active sequence-viewer region – the current active region within the associated sequence
• Adjacent flexible residues (initial default 1) – how many additional residues next to each end of the missing segment or specified region to remodel relative to the input structure. If the residues designated as flexible are different types in the sequence than in the structure, the residue types in the sequence will be used.
• Computation location
  • web service (initial default) – run the Modeller web service hosted by the UCSF RBVI; the user must provide:
    • Modeller license key – see above
  • local machine – run a local installation of Modeller; the user must install Modeller version 10 or newer, then provide:
    • Executable location – the pathname of the Modeller executable

Advanced settings:

• Use fast/approximate mode (produces only one model) (initial default off) – use fast/approximate mode (~3 times faster) to get a rough idea of model appearance or to confirm that the alignment is reasonable. This mode does not randomize the starting structure (generates only a single model) and performs very little optimization of the target function.
• Protocol – which loop-modeling protocol to use:
  • standard (initial default) – evaluate conformations by the sum of all restraints
  • DOPE – Discrete Optimized Protein Energy score (DOPE, see Shen and Sali, Protein Sci 15:2507 (2006)) with Lennard-Jones potential and GB/SA implicit solvent interaction. The DOPE protocol generally gives higher-quality results than the standard protocol, but is more computationally expensive and more prone to calculation failure, potentially resulting in fewer models than requested.
  • DOPE-HR – the same as DOPE, except with higher precision
• Temporary folder location (optional) – use the specified location for temporary files; otherwise, a location will be generated automatically

Model Loops settings including the license key are automatically saved in the preferences. Other than the license key, the remembered settings apply only to the GUI; the command defaults are not changed.

Clicking Cancel simply dismisses the dialog, whereas OK sends information to the web service and initiates the calculation.

The results dialog is the same as described for Modeller Comparative.