3. Monodentate and Bidentate Interaction Patterns Between Protein Carboxylates and Benzamidino / Guanidino Groups in Ligands.
With Relibase+ it is possible to find existing interaction patterns between benzamidino and
guanidino groups of ligands and carboxylate residues of proteins.
Whereas nearly all benzamidino groups form bidentate salt bridges with Asp189 of serine
proteinases, there are only few forming monodentate interactions. In the latter case only
one nitrogen of the benzamidino residue forms two charge assisted hydrogen bonds to the
oxygen atoms of Asp189 (e.g. the inhibitor 4-TAPAP, PDB-code 1ETT).
The guanidino group with its three nitrogen atoms can form both monodentate as well as bidentate
salt bridges with the carboxylate function of the protein.
Search for benzamidines
- Open the MolEd editor by pressing the 2D/3D button.
- Draw the benzamidine fragment (ligand in Molecule Type menu) and the protein's
carboxylate group (protein in Molecule Type menu). Use the template for the
phenylring (Group menu) and the bond type any for connections between N-C and O-C,
respectively.
- Define the two distance criteria between the nitrogen and oxygen atoms using the Distance
command. The range of the two distances can be changed in the Constraints menu. To find
only bidentate entries select 0.5 A for the lower limit (default) and 3.3 A for the upper limit.
- To superimpose the carboxylate group highlight the carbon and two oxygen atoms with
Select. These atoms are colored in red.
- Save the query as benzam1 in the Save in Hitlist field.
- To exclude all NMR structures from the search query set the Min. Resolution to 0
(Resolution of NMR structures are set to -1).
- Start the search with Submit. Activate the Superimpose hits on selected atoms
before submitting.
- A new browser window shows the result of this query.
- Click on Launch in the 3D Visualizer toolbox to open a RasMol window with the
first entry of the hit list.
- To see the Superposition of the results press Superposition. The recognition
pattern will be shown in the RasMol window. The benzamidine groups distribute in a distinct
and limited area. The display option of RasMol can be changed at the pop-up menu
Display. The next picture shows the superposition with the Wireframe option.
Search for guanidines
The search query of interactions between ligands containing guanidine and protein carboxylate groups is performed in a way similar to the query above.First the carboxylate fragment (protein in Molecule Type menu) and the guanidino group are drawn with the MolEd editor. To restrict the number of hits only arginine fragments are searched.
Two distance criteria are defined similar to the bidentate benzamidine example (lower limit 2.3 A and upper limit 3.5 A for both distances). All other settings are performed as in step 4 to 9 of the benzamidine search.
To view the superimposed hits activate the Superposition button. In comparison to
benzamidine the guanidine group around the carboxylate is spread over a wider range of area.
The distribution of distances between the carboxylate and guanidino group can be displayed
with the Distribution Histogram tool. The most frequent distances lie in a range
between 2.7 and 3.1 A.
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