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Structural Bioinformatics Overview: Methods and Applications

Explore research on geometric algorithms, protein structures, and molecular docking. Learn about PXR, protein folding, and electron density modification. Gain insights into structure determination, geometric models, and lattice chain growth algorithms.

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Structural Bioinformatics Overview: Methods and Applications

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  1. Research Overview III Jack Snoeyink UNC Chapel Hill

  2. Geometric algorithms in: • Docking (Redinbo) • PXR [Leaver-Fay, Berretty] • Dynamic representations [Hsu] • p-fold (Latombe) • Hinge determination in TripRS (Carter) • Folding (Tropsha) • Scoring with Delaunay [O’Brien,Bandyopadhyay] • Mining structure DB • Structure determination (Carter) • Electron density modification [Carr,Kettner,Mascarenhas] • Packing (Edelsbrunner) • Alpha-shapes, skin surfaces [Kettner,Mascarenhas]

  3. Other branches: • Surface representation [Isenburg] • Compression of geometric models • Topology for visualization (LLNL) • [Mascarenhas, Carr]

  4. PXR: Pregnane Xenobiotic Receptor SR12813

  5. PXR with bound ligand Ball & stick / van der Waals spheres Model diagram Solvent accessible surface Diagramatic representations

  6. Geometry on computers • Where we can see structure, shape, connections, regions, • The computer sees only coordinates • For example, this PXR protein & ligand is in the Protein Data Bank as…

  7. 2380 lines later… ATOM 2395 O HOH 1600 29.442 64.461 -1.726 1.00 66.79 8 ATOM 2396 O HOH 1601 19.427 85.921 -22.662 1.00 60.16 8 ATOM 2397 O HOH 1602 5.344 90.815 7.154 1.00 54.96 8 ATOM 2398 O HOH 1603 -14.216 50.571 5.561 1.00 54.96 8 ATOM 2399 O HOH 1604 5.533 45.964 0.404 1.00 62.55 8 ATOM 2400 O HOH 1605 -1.394 63.145 20.705 1.00 40.08 8 ATOM 2401 O HOH 1606 -2.578 54.566 22.874 1.00 57.40 8 ATOM 2402 O HOH 1607 3.600 69.196 22.807 1.00 54.51 8 ATOM 2403 O HOH 1608 6.139 65.007 -18.611 1.00 54.86 8 ATOM 2404 O HOH 1609 4.202 75.224 -27.568 1.00 58.04 8 ATOM 2405 O HOH 1610 -5.421 61.703 24.061 1.00 57.88 8 ATOM 2406 O HOH 1611 -11.943 45.372 11.041 1.00 62.72 8 END HEADER GENE REGULATION 08-MAY-01 1ILG TITLE CRYSTAL STRUCTURE OF APO HUMAN PREGNANE X RECEPTOR LIGAND . . AUTHOR R.E.WATKINS,M.R.REDINBO . . ATOM 1 C GLY 142 -5.808 44.753 13.561 1.00 58.97 6 ATOM 2 O GLY 142 -5.723 45.523 14.515 1.00 59.54 8 ATOM 3 N GLY 142 -4.377 43.177 14.842 1.00 59.37 7 ATOM 4 CA GLY 142 -5.307 43.330 13.685 1.00 59.68 6 ATOM 5 N LEU 143 -6.324 45.108 12.387 1.00 58.87 7 ATOM 6 CA LEU 143 -6.839 46.455 12.152 1.00 58.50 6 ATOM 7 CB LEU 143 -6.483 46.907 10.736 1.00 57.90 6 ATOM 8 CG LEU 143 -5.849 48.290 10.555 1.00 57.77 6 ATOM 9 CD1 LEU 143 -4.599 48.411 11.407 1.00 56.51 6 ATOM 10 CD2 LEU 143 -5.505 48.492 9.090 1.00 56.92 6 ATOM 11 C LEU 143 -8.352 46.446 12.333 1.00 58.92 6 ATOM 12 O LEU 143 -9.046 45.640 11.714 1.00 59.85 8 ATOM 13 N THR 144 -8.862 47.341 13.174 1.00 58.88 7 ATOM 14 CA THR 144 -10.299 47.407 13.444 1.00 59.76 6

  8. Pregnane Xenobiotic Receptor (PXR) Implicated in drug-drug interactions with St. John’s wort

  9. PXR binding pockets

  10. Successes: • Educating ourselves • Collaboration with Biochemistry • Software integration and library building [Kettner, Hsu, …] • Partial results

  11. SR12813 Results Algorithm Crystal

  12. Coumestrol results

  13. Difficulty • Validation: • Molecular dynamics with standard energy models • Most are designed for proteins • Evaluate against AutoDock • general search by simulated annealing with many parameters • Crystallize with other bound ligands • Incorporating flexibility

  14. Pfold: probability of folding [Du, et al. 98] 1- Pfold Pfold folded state unfolded state

  15. Domain motion of TrpRS . • Biological motivation:Understand the enzymatic mechanism • Computational motivation:Compute motion for objects with many degrees of freedom TrpRS

  16. Difference in torsional angles • Local • O(n) running time • Difference in RMS distances • Global • O(n3) running time Previous work

  17. Random variations • Random variations due to • Thermal motions • Measurement errors • How to choose thresholds to detect significant torsional angle changes? • Want • Robust: differentiate statistically significant changes from random variations • Efficient: O(n logn) running time

  18. Distribution of random variations of RMS distances • Minimum RMS distance • Assumptions: • The effect of minimization is small. • X, Y, Z have errors with Gaussian distribution

  19. Distribution of random variations of RMS distances • Density function of : • For and ,

  20. Convex hull formed by the tetrahedral edges Each tetrahedron corresponds to a cluster of four residues Four-Body Statistical Potential [O'Brien] • Statistical potential based on quadruples of nearby residues identified by Delaunay Tessellation

  21. Find quads incrementally • Previous implementation could not use 4-body due to tessellation cost. • Incremental algorithm in existing code already produces 2-3 orders of magnitude improvement. • Rewrite in progress should be even faster.

  22. Lattice Chain Growth Algo. • Cubic lattice (311) w/ 24 possible moves {(3,1,1),(3,1,-1),…,(-3,1,1)} (Gan, Schlick, Tropsha) • Grow chain by Monte Carlo, choosing next position based on empirical statistical potential.

  23. 4-tuples that may become Delaunay by perturbing points by at most e>0. Check robustness of statistical potential Search for motifs Almost-Delaunay tetrahedra [Bandyopadhyay]

  24. Electron density refinement • Structure from x-ray diffraction experiments • Squaring relations give more accurate localization • Combine information on fragments to further refine • Talk by Carter.

  25. Surface Mesh Compression [Isenburg]

  26. Topology for visualization [Mascarenhas]

  27. UNC-CH Graphic Lab: NIH res. for molecular graphics

  28. PXR p-fold TrpRS motion Delaunay-based statistical potential Fast evaluation MC chain growing Almost Delaunay Electron density refinement Surface compression Visualization Bio shape representation shape classification docking structure determination Modeling shape representation Algorithms deformation/flexibility motion planning Software library effort visualization I've mentioned:

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