1. Predicting ligand binding sites on protein surface

2. What is the binding site?
(Concave, cleft, hole) – shaped region on protein surface
A key into a lock!
Key-ligand
Lock-protein
Lock hole-binding sites

3. Why do we need to find binding sites?
First step in many structure analyses:
Functional/catalytic site prediction
Comparisons of protein atomic configurations
Docking calculations
Structure-based drug design …

4. Algorithms for finding binding sites
Grid-based
Cover the protein into a 3D grid,
Empty grid points are then defined a pockets if they satisfy a number of geometric or energetic conditions.
Sphere-based
A set of probe spheres are placed on protein surface.
Pocket spheres are those generated probe spheres that satisfy a number of geometric conditions among the generated probe spheres.
α-shape based
Is defined as a subset of Delaunay tessellations of protein atoms, omitting edges longer than the sum of the radii of two atoms.

5. Algorithms for finding binding sites
Grid-based
POCKET, LIGSITE, LIGSITECS ,LIGSITECSC ,ConCavity, PocketPicker and GHECOM
Sphere-based
SURFNET, PASS, Q-SiteFinder, PHECOM
α-shape based
CAST, Fpocket

6. Delaunay tessellations
α-shape
The shape surrounded
by the black line
The edge of
Delaunay tessellations

7. Delaunay tessellations
No edge that its length is
longer than the sum of the
radii of two atoms

8. α-shape based: CAST
Computes a triangulation of the protein’s surface atoms using α-shapes, then triangles are grouped by letting small triangles flow toward neighboring larger triangles, which act as sinks!

9. Grid-based
The protein is projected onto a 3D grid. They focused on PSP (protein-solvent-protein) events of the grids.
When a straight line drawn from a grid point is enclosed on both side by protein atoms, the arrangement of the line for that grid point is termed a PSP event.
Grid points having more than a threshold number of PSP events are defined as pockets.

10. Sphere-based SURFNET:
Places a sphere (called gap spheres) between two protein atoms.
If the sphere contains any other atoms, reduce its radius until it just touches one protein atom.
A set of these gap spheres are defined as pockets.

11. To define pocket region on
Grid-based: GHECOM
By Takeshi Kawabata
Kawabata T. (2010) Detection of multi-scale pockets on protein surfaces using mathematical morphology. Proteins,78,
To define pocket region on
protein surface

12. Primary points:
A new definition of pockets by using the basic operations of mathematical morphology
Proposed an algorithm for finding pockets
Construct a useful dataset for algorithm testing
Introduced a new method for evaluate binding site predictions
Some useful discoveries about ligands bind to binding sites

13. Some Background: Multiscale pockets: “Size” and “Depth” of pockets:
Calculate deep and shallow pockets simultaneously
“Multiscale pockets” need “multiscale probes”, they use many probes of different sizes to define pockets.
“Size” and “Depth” of pockets:
Two properties of pockets
A definition of pockets using small and large spherical probes of his previous work: PHECOM
A pocket region: a space into which a small spherical can enter but a large spherical probe cannot.

14. Mathematical Morphology
Pocket definition
Mathematical Morphology
It is a theory used in the analysis of geometric features of digital images based on rigorous set theory.
Morphology can provide boundaries of objects, their skeletons, and their convex hulls. It is also useful for many pre- and post-processing techniques, especially in edge thinning and pruning.

15. mathematical morphology (con.)
Four operations: dilation, erosion, opening, closing
a: Molecular shape
b: The shape of the probe
c:X⊕P: Operation dilation of X by P
d:XΘP: Operation erosion of X by P
e:X○P: Operation opening of X by P
f: X • P: Operation closing of X by P
The shape X is the vdW volume of a
protein