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1. Target definition

All tools in the ProteinsPlus server work on a structure of a protein or a nucleic acid. In the first step, you need to define this structure either by selecting a structure form the Protein Data Bank (PDB) via its PDB code (e.g. 1a99) or upload any other structure in PDB format. Additional ligand molecules can be provided in SDF format.

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2. Tool selection

Afterwards you can select the tool you are interested in. You can choose GeoMine either by selecting it from the drop-down menu or by following the link under the respective tool description.
General mouse/keyboard controls for the 3D viewer include the rotation/translation/zooming of the scene, inspection of atom/bond infos and execution of structural measurements.

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3. Set Structure visualization for 3D query selection

GeoMine performs textual, numerical and 3D searches in pockets of the entire PDB dataset. Possible use cases are the search for ligands for a given pocket or off-target proteins for a given ligand. Prepare the visualization in the 3D viewer to facilitate the 3D query selection:
E.g. select and focus a precalculated pocket entry from the "Pockets" tab, set all "Representation Options" below the 3D viewer to "Off" in order to visualize only the pocket, use "Toggle Viewer Size" (try fullscreen) and set "Background" to "White".
Besides the 3D query, a GeoMine search might also contain a PDB subselection, which restricts the search to a user-defined set of PDB codes, and filters for textual/numerical properties of any component of the PDB, e.g. the enzyme class or the hydrophobicity of a pocket. All query types can be used independently or in combination.
Click "Search" in any of the query tabs to start the GeoMine search.
Click "Export query/Import query" for saving and reloading a query
Click "Rest-service XML" for saving a query as XML usable by the GeoMine REST-serivce.

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4.1 3D query selection

The 3D viewer allows the construction of queries from scratch and based on the 3D representation of an existing PDB structure or its pockets. You can select the 3D query in any structure, the most convenient way is to select it in a precalculated pocket from the "Pockets" tab. The precalculated pockets are processed by Protoss, DoGSiteScorer and GeoMine during calculation. Empty pockets with a volume less than 100 cubic angstrom are excluded and their number is limited to twice the number of chains. If DogSite could not calculate a pocket for a ligand, the radius pocket (6.5 angstrom) of the ligand is added. The pockets contain water molecules, ions, ligands, other small molecules and interactions of the following types: H-Bond (blue), Ionic (magenta), Metal (yellow), Pi-Cation (green), Pi-Pi (cyan). Furthermore, selectable GeoMine features (binding site surface atoms, aromatic ring centers and normals, end/mid alpha carbon atoms and directions of helices and strands) are visualized.
The pocket can be switched on and off guiding the 3D query design. The 3D query is visualized in the 3D viewer and in tables for further modification of chemical and geometrical properties. Main properties like the element name of a point are automatically set. The automatic loading of all other, more discriminative properties can be activated with the checkbox "Point selection with all properties". For a valid 3D query, all points must be part of at least one point to point constraint.

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4.2 3D query selection

Choose a selection mode in order to select a 3D query in the 3D viewer.
Point: Define points by clicking on (surface) atoms and point features (aromatic ring center, secondary structure mid/end alpha carbon atoms). Surface atoms are represented by non transparent big spheres. Undefined points can be added clicking on an unoccupied position in the 3D viewer. These points can subsequently be translated in the 3D viewer to the desired position, if the point is not connected by point-point constraints. In order to specify an undefined point as aromatic ring center, its "Element" must be set to "Any" and its "Type" to "Aromatic Ring Center". The selected points can be further specified by different attributes.
Distance/Interaction: Point-point constraints (distances and interactions) can be defined by clicking on a pair of points. They can also be added directly by clicking on atoms, aromatic ring centers and secondary structure points. The corresponding points are automatically added. The interaction type (e.g. Ionic) and point types (e.g. Cation/Anion) will be automatically set, if an interaction is available between the points. The default tolerance value is 0.5 A and preset for each added distance range. Distance length and tolerance can be modified by the user.
Angle: Angle constraints can be defined between connected point-point constraints clicking on these two. Also ring normals of aromatic ring centers and directions of secondary structure features can be used for angle definition. The preset tolerance is 15 degree. Angle size and tolerance can be modified by the user.
Hide the precalculated pocket in order to facilitate the selection of point-point constraints and angles between already set points.
For achieving a short search time, the following rules are useful:
(1) Set as many properties of 3D query as possible, e.g. define a protein point (backbone or sidechain);
(2) Choose rarely occurring attributes for the 3D query, e.g. prefer the selection of N instead of C backbone atoms;
(3) Add as many textual/numerical properties as possbile;
(4) Add as many distance and interaction constraints as possible;
(5) Choose small distance tolerances in close proximities.


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5. Textual / numerical property filter selection

Textual and numerical properties can be added to a table. The filters can be negated and all defined filters have to be fulfilled for a match. For the textual filters, a list of properties can be defined. Here a match must fulfill only one of these properties. You can inspect a description of the filter that is currently selected in the dropdown by hovering over the info icon next to it.

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6. PDB codes selection

Put PDB codes (case insensitive) into the respective text box to limit the search on a PDB subselection. Please separate the PDB codes by newlines. If the text box is empty, the complete database will be searched. Using the result refinement feature, all resulting PDB codes that matched the search criteria are loaded into this text box for further refinement of the search and results.

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7. Result

An search process of successive query modifications and result analyses can be performed using the refinement and history functionality. The results can be refined continuing the search in all found PDB codes and with the current 3D query as a new starting point. The results history allows browsing through prior and successive search results obtained by refinement.
Visualizable results are presented in the results table. They can be displayed in the 3D viewer individually or together as superimpositions for visual analysis with different representation options. The number of visualizable results is limited to 150, the downloadable search statistic report however includes all detected results. If the search contains a 3D query, the results table is initially sorted by RMSD. The RMSD is calculated considering the 3D query points and the respective result points that match the 3D query points.
The table can be searched, e.g. with respect to the PDB title, and its entries sorted, e.g. by their enzyme classes. Besides the visual analysis of hits, a search statistics report containing common structural aspects of the complete results list as well as the pocket .pdb files and the table content as .json and .csv files of the 150 visualizable results can be downloaded.
If you want to access your results later (max 30 days), you can copy a link to the results.

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