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CAPRI

CAPRI. Critical Assessment of Prediction of Interactions. CAPRI docking targets. CAPRI-01 (unbound/unbound) Lactobacillus HPr kinase - B. subtilis HPr CAPRI-02 (unbound/bound) bovine rotavirus VP6 - Fab CAPRI-03 (unbound/bound) flu hemagglutinin - Fab HC63. Critical points selection.

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CAPRI

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  1. CAPRI Critical Assessment of Prediction of Interactions

  2. CAPRI docking targets • CAPRI-01 (unbound/unbound) Lactobacillus HPr kinase - B. subtilis HPr • CAPRI-02 (unbound/bound) bovine rotavirus VP6 - Fab • CAPRI-03 (unbound/bound) flu hemagglutinin - Fab HC63

  3. Critical points selection Matching of critical points Clustering and Scoring Docking Algorithms Flow Molecular Surface representation Active site knowledge

  4. Budda Connoly surface for grid distance function calculations Shuo points as critical points Kely Connoly surface as critical points Molecular Surface Representation

  5. Budda Volume function is computed for each shuo point and knobs and holes are selected. Kely Volume function is computed for each point and local minimum and maximum of knobs and holes are selected. Critical Points Selection

  6. Both algorithms use Pose-Clustering technique: For each triangle of receptor compute the transformation to each ligand matching triangle. Cluster transformations. Score the results. Complexity: O(m3n3) Matching of Critical Points

  7. Budda Each reference frame is defined by one critical point (knob, hole) and two it’s neighbors. The signature includes triangle sides length, the angles a1, a2 and torsion angle w for AB and AC. Kely Each reference frame is defined by 2 points (knobs,holes) and their normals. The signature information includes the distance between two points, the angles a1, a2 and torsion angle w. w a1 a2 B A C Reference Frame Selection

  8. Budda Knob matches hole for one point only, not necessary for neighbor points. The difference between distances (AB,AC,BC) < d_thr. The difference between the angles < angle_thr. Complexity: O(m3n3) Kely Knob matches hole for every point. The difference between distances < d_thr. The difference between the angles < angle_thr. Complexity: O(m2n2) w a1 a2 B A C Reference Frame Complementarity

  9. Budda At first fast clustering by transformation parameters is performed. For final results, the RMSD clustering on the interface is applied. Kely The transformations are clustered by the rotational angle between every two conformers. Clustering

  10. Budda A number of ranges on the surface of receptor molecule is defined: < -2 |-2:-1.5|-1.5:-1| -1:1 |1:1.5| >1.5 For each interface number of surface (shuo) points in each range is computed. The score is a weigted function of each layer. In addition, number of penetrating residues is computed and added to the score. Geometric Scoring • Kely • Only 3 ranges are used: • Surface, Exterior, Core. • The score is given as: • GS=S-4E-C2/(1+e6-C) • Additional geom. score: • NS = GS/S • Electrostatic “clashes” filter • Connected components of interface filter.

  11. HPr kinase/phosphatase is a key regulatory enzyme controlling carbon metabolism in bacteria. The protein is a hexamer. HprK/P contains the Walker motif - characterisctic of nucleotide-binding proteins Capri1:enzyme – inhibitor

  12. Capri1:enzyme – inhibitor

  13. It catalyses the ATP-dependent phosphorelation/dephosphorelation of Ser46 in HPr. Capri1:enzyme – inhibitor

  14. The docking was done using Walker motif and Ser46 as active site, so that only relevant solutions could be created. Capri1:enzyme – inhibitor • The filter on the distance between phosphate and oxygen atoms of Asp was applied. Only relevant solutions were selected.

  15. Viral capsid: Capri 2 and Capri3- biology background

  16. Capri2 - VP6 protein of rotavirus that causes gastroenteritis in children. Capri3 – influenza hemagglutinin. biology background …

  17. Capri 2

  18. Trimmer. (symmetry) The surface of the B (helices) domain is buried in rotavirus capsid. The H-domain interacts with the antibody. A ‘hint’ was given- to use the trimmer in the docking, meaning that active site is expanded to more than one chain. Capri2 antigen ...

  19. Capri 3

  20. Hexamer. 3 dimmers (symmetry) One chain of the dimmer(s) is buried in the capsid Other antibody-antigen complexes of this antigen also implies active site is in the ‘external’ chains (B,D and F) Capri3 antigen ...

  21. The antibody active site is always in the CDRs, which are in the variable part of the antibody CDRs H3 and L3 are most likely to be in the active site. At least 4 CDRs in the active site Antibodies - CDRs

  22. The light and heavy chain has conserved areas which enables us to align a given sequence to a consensus sequence which was built using statistical data. This alignment is then used to locate the CDRS area. This information may be used in docking programs, in the docking process itself (budda) or in a filtering process (kely). CDRs location utility

  23. Antibodies active sites have a high propensities of Tyr,Trp and Arg. This property may be used to filter out docking results or even be used in the scoring function. (we used both) Antibodies Tyr, Trp and Arg propensities

  24. Both antigens (and also the capri1 enzyme) have a rotational symmetry. ‘rmsd-like distance function’ Clusterring is used to gather transformations which are symmetrically similar. Symmetry

  25. Clustering different alg results • Any algorithms performs well on some targets and less on other. • Since 10 results should have been submitted to each target it seemed reasonable to gather results from different algorithms, re-score them, and then re-cluster them.

  26. Critical points selection Matching of critical points Clustering and Scoring CAPRI Docking Flow • Compute Connolly and Shuo surface representation. Molecular Surface representation • Compute CDRs in case of Antibody-Antigen docking. • Select knobs and holes for CDRs only • Match critical points - use 2 points and their normals for faster matching. • Cluster transforms. • Compute geometric score. • Apply CDRs, Tyr-Trp, NS, interface connectivity, symmetry filters.

  27. Enzyme – inhibitor test set results (unbound)

  28. Antibody-Antigen test set results (unbound/bound)

  29. MoleculeGrid class - new class in GAMB++ library. The class can compute molecule grid with distance function, volume function and normals for critical points. CDR utility - utility that finds CDRs for antibody, by aligning new sequence to consensus sequence. Symmetry and Clustering utility New docking version of budda - including new grid representation, two points and normals matching. New classes and utilities

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