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SimBioSys Inc.© 2001http://www.simbiosys.ca/ New methods for studying receptor-ligand interactions Zsolt Zsoldos, Aniko Simon SimBioSys Inc.,

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Presentation on theme: "SimBioSys Inc.© 2001http://www.simbiosys.ca/ New methods for studying receptor-ligand interactions Zsolt Zsoldos, Aniko Simon SimBioSys Inc.,"— Presentation transcript:

1 SimBioSys Inc.© 2001http://www.simbiosys.ca/ New methods for studying receptor-ligand interactions Zsolt Zsoldos, Aniko Simon SimBioSys Inc., http://www.simbiosys.ca/http://www.simbiosys.ca/ Efficient grid-based force field calculations on protein structures to evaluate, visualise and help to improve the binding of lead structures.

2 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Contents of the presentation Next generation grid technology Configurable interaction force fields Force field visualisation techniques Results on Trypsin - APPA Ras P21 - GDP COX2 - SC558

3 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Grid resolution problem 1.6Å 7K points 0.3 MB 0.22 min 50% error 1.0Å 30K points 1.3 MB 1 min 20%error 0.5Å 250K points 11 MB 8 min 8% error 0.16Å 7300K points 321 MB 216 min 2% error

4 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Variable resolution grids Grid spacing 0.15 Å -3.0 Å Memory and CPU (build) ~1 Å -1.5 Å grid equivalent Precision for ligand atoms ~0.15 Å grid equivalent Octree, hashing Hierarchical grid: constant access time 0.15Å-3.0Å variable 28K points 1.5 MB 1 min 2%

5 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Interaction Force Fields 1. Van der Waals: Lennard Jones Electrostatics: Coulomb Parameters based on AMBER Partial charges of H-bond acceptors are distributed to the lone pairs at 1 Å distance from the heavy atom Lp O C - -

6 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Interaction Force Fields 2. Hydrogen bond term: A-H and D-Lp distances Proton directionality: cos 2  D-H-A) Lone pair directionality: cos(A-Lp-H) Optimum directionality vectors Multiple receptor atom effects Separate donor, acceptor grids D H A Lp

7 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Interaction Force Fields 3. Hydrophobicity term: Distance dependent functions (e.g. Lennard-Jones) Polar repulsion component Clash penalty component Activity flags (assigned using knowledge base) Highly configurable setup Smooth functions

8 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Force field visualization techniques 2D surfaces Molecular surface map Contour iso-surface Color coded cut plane True 3D visualisation Volume rendering

9 SimBioSys Inc.© 2001http://www.simbiosys.ca/ APPA electro and H-bond fields with Volume Rendering

10 SimBioSys Inc.© 2001http://www.simbiosys.ca/ APPA H-bond donor field visualisations

11 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Trypsin forces compared to APPA atoms

12 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Ras P21H-bond acceptor field with GDP

13 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Ras P21 H-bond donor field with GDP

14 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Ras P21 electrostatic and H-bond fields compared to GDP ligand atoms

15 SimBioSys Inc.© 2001http://www.simbiosys.ca/ COX- 2 hydrophobicity field with SC558

16 SimBioSys Inc.© 2001http://www.simbiosys.ca/ COX-2 electrostatics with SC558

17 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Conclusion "No compromise" solution to eliminate the well known grid resolution problem Force Field validation - looking for collaborators Volume rendering is "The Ultimate" solution for 3D force field visualisation - now available with interactive speed on cheap PC hardware The “InterView” software

18 SimBioSys Inc.© 2001http://www.simbiosys.ca/ Acknowledgements Timur Skeini, Irina and Zsolt Szabo Peter Johnson & ICAMS - consultations Linux community - development platform nVidia, ATI etc. - fast volume rendering The organizers - opportunity The audience - attention and patience

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