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New methods for studying receptor-ligand interactions

New methods for studying receptor-ligand interactions. Zsolt Zsoldos, Aniko Simon SimBioSys Inc., 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.

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New methods for studying receptor-ligand interactions

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  1. New methods for studying receptor-ligand interactions Zsolt Zsoldos, Aniko Simon SimBioSys Inc., 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. 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. 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. Variable resolution grids • Grid spacing 0.15Å-3.0Å • Memory and CPU (build) ~1Å-1.5Å grid equivalent • Precision for ligand atoms ~0.15Å grid equivalent • Octree, hashing • Hierarchical grid: constant access time 0.15Å-3.0Å variable 28K points 1.5 MB 1 min 2%

  5. 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 1Å distance from the heavy atom Lp Lp - - O C

  6. Hydrogen bond term: A-H and D-Lp distances Proton directionality: cos2(D-H-A) Lone pair directionality:cos(A-Lp-H) Optimum directionality vectors Multiple receptor atom effects Separate donor, acceptor grids Interaction Force Fields 2. A Lp H D

  7. 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. 2D surfaces Molecular surface map Contour iso-surface Color coded cut plane True 3D visualisation Volume rendering Force field visualization techniques

  9. APPA electro and H-bond fields with Volume Rendering

  10. APPA H-bond donor field visualisations

  11. Trypsin forces compared to APPA atoms

  12. Ras P21H-bond acceptor field with GDP

  13. Ras P21 H-bond donor field with GDP

  14. Ras P21 electrostatic and H-bond fields compared to GDP ligand atoms

  15. COX- 2 hydrophobicity field with SC558

  16. COX-2 electrostatics with SC558

  17. 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. 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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