Module 2: Structure Based Ph4 Design. MOE provides several applications to analyze protein information in absence of ligands: The Site Finder ( using the binding site of a receptor to generate the query) Contact preferences In part b) of the SBDD course: The MCSS algorithm for de-novo design
MOE provides several applications to analyze protein information in absence of ligands:
In part b) of the SBDD course:
The Site Finder screens the surface of a protein for potential binding sites. In addition to locating cavities it also indicates preferred locations for hydrophilic or non-hydrophilic interaction points.
Site Finder considers the relative positions and
accessibility of the receptor atoms along with a
rough classification of chemical type. The
method applies alpha spheres. This is aspecial
case of a contact sphere that circumscribes 4 atoms on its boundary and contain no internal atoms. Centers of alpha spheres are clustered into hydrophobic and hydrophilic areas.
Geometric analysis of a molecule
by red centroids
non-hydrophilic) are colored white.
Site: Site number
Size: Number of contributing spheres
Hyd: Number of hydrophobic atoms contacted in receptor
Side: Number of sidechain contact atoms
Residues: Residues at local surface
Atoms included in the calculation
Display mode of alpha spheres
Display mode of site(s); Residue selection option
Creates dummy atoms
Minimum sphere radii to detect (non-) LP-active atoms
Distance filter before clustering
Settings for alpha sphere clustering
4. Examine the different sites. The 2nd site has more receptor contacts but fewer hydrophobic contacts.
5. Select the first site. To restrict the view to the immediate environment by selecting Isolate: “Atoms” and enable SE Residues.
Ensure that (MOE |Selection | Synchronize) is ON. Invert the selection (MOE | Selection | Invert) and delete all hidden residues.
6. Keep the positions of the Alpha Centers by pressing “Dummies” and close the panel.
7. To increase the size of the dummy atoms <Ctrl>-click on one of the dummy atoms to select all of them. Select (Render | Space Filling).
Red: Potential hydrophilic contact areas
8. Create a surface for the pocket using (MOE | Compute | Surfaces and Maps).
9. In the panel, keep default settings but select
Near: Dummy Atoms
The colours of the surface displays those regions of the receptor surface suitable for a hydrogen bond or metal-lone-pair interactions.
Try also different surface color schemes to compare the results or modify the transparency (TF, TB) settings.
10. Save the pocket as 1ke6_pocket.moe
Non-bonded protein-ligand interactions are analyzed with respect to distance, angle and out-of-plane preferences. The receptor and ligand atoms are classified into atom types and the experimental histograms of the contacts are fitted by analytical functions. Contour maps display likelihood ratios for hydrophobic over hydrophilic preferences (green) or vice versa (red).
v taken from pi system
AReceptor Atom Classification
T_nQ2: HYD (50%)LPA (50%)
HYDLPAr lognorm 12-6a gamma cauchyp gamma cauchy
Contact preferences can be used to generate or refine a Ph4 query.
The suggestions for preferred interactions in the binding site may be used to derive a Ph4 query in absence of any known ligands.
5. Once finished creating features, an excluded volume may be added.*)Use a surface representation to guide the adjustment of tolerances for the excluded volume.
Module 3: Structure-based design with known actives and structural binding site details
If structural information about both proteins and their ligands is available, the essential (conserved) protein ligand interactions (e.g. H-bonds) can be identified and used to focus on the key Ph4 features. Since those interactions include “projected” protein interaction sites, the results should be more meaningful than a small molecule alignment in itself.*)
MOE provides several applications to analyze protein-ligand information:
In the Protein course: