1. SciPy2004 FlexTree Package Yong Zhao The Molecular Graphics Laboratory The Scripps Research Institute,La Jolla,CA for computational biology

2. SciPy2004 Overview  Background  FlexTree package  Development  Application of FlexTree  Summary

3. SciPy2004 Docking Study  ‘Lock and Key’ model  Induced Fit –50% of dockings fail because of induced-fit

4. SciPy2004 Background  Biological Molecules –Large conformational space  Docking Study –docking related conformational sub-space is relatively small –still too large to explore explicitly

5. SciPy2004 Example

6. SciPy2004 FlexTree Basic Objects Tree Node Shape Motion Shape-Motion Convolution Shape Combiner

7. SciPy2004

8. <root file="1hvrLigRotated.pdbqs" name="1hvr" id="99" selectionString="1hvrLigRotated" convolve="FTConvolveApplyMatrix"> <node name="chainA" id="1" selectionString="1hvrLigRotated:A" convolve="FTConvolveApplyMatrixToCoords"> <node name="CoreA" id="2" selectionString="1hvrLigRotated:A:,PRO1-GLU34,…“ motion="FTMotion_Generic“ motionParams="matrixList:list float 0.995 0.078…“ shape="FTLines“ shapeParams="cutoff:float1.85" convolve="FTConvolveApplyMatrixToCoords"> <node... XML

9. SciPy2004 Programming  Python –PMV (Python Molecule Viewer) –Vision (Previously know as ViPEr ) –SciPy (Genetic Algorithm package)  C++ –Scoring function –Computational intensive

10. SciPy2004 Application of FlexTree Searching the conformational sub-space

11. SciPy2004 FlexTree-based Computations Automated Docking

12. SciPy2004 Genetic Algorithm Hinge Float: hinge angle Genome The motion parameters are used as ‘Genes’

13. SciPy2004 Docking Test Result  Population size = 500, converges after 91 generations  the best docked conformation –interaction energy : -21.35 Kcal/mol –compare with experimental result : -20.7 Kcal/mol –RMSD = 0.35 Å (all atoms ) v.s. crystal structure

14. SciPy2004 FlexTree Summary  Represents the flexibility hierarchically ✔ Given knowledge of protein flexibility ✔ Conformational sub-space ✔ Tree structure  Real-time 3D Visualization  Python & C++  Conformation search & Docking test  http://www.scripps.edu/~sanner/python

15. SciPy2004 Acknowledgment - Dr.Michel Sanner - Dr.Daniel Stoffler - The Molecular Graphics Lab @ TSRI - SciPy community - NBCR National Biomedical Computational Resources - NIH Grant BISTI,R21/R33GM65609