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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. - PowerPoint PPT Presentation
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SimBioSys Inc.© 2001http://www.simbiosys.ca/
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.
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
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
SimBioSys Inc.© 2001http://www.simbiosys.ca/
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 variable28K points1.5 MB1 min2%
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 1Å distance from the heavy atom
Lp Lp
O
C
- -
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Interaction Force Fields 2.
Hydrogen bond term: A-H and D-Lp distances
Proton directionality: cos2D-H-A) Lone pair directionality: cos(A-Lp-H)
Optimum directionality vectors
Multiple receptor atom effects
Separate donor, acceptor gridsD
H
A
Lp
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
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Force field visualization techniques
2D surfacesMolecular surface mapContour iso-surfaceColor coded cut plane
• True 3D visualisation• Volume rendering
SimBioSys Inc.© 2001http://www.simbiosys.ca/
APPA electro and H-bond fields with Volume Rendering
SimBioSys Inc.© 2001http://www.simbiosys.ca/
APPA H-bond donor field visualisations
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Trypsin forces compared to APPA atoms
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Ras P21H-bond acceptor field with GDP
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Ras P21 H-bond donor field with GDP
SimBioSys Inc.© 2001http://www.simbiosys.ca/
Ras P21 electrostatic and H-bond fields compared to GDP ligand atoms
SimBioSys Inc.© 2001http://www.simbiosys.ca/
COX- 2 hydrophobicity field with SC558
SimBioSys Inc.© 2001http://www.simbiosys.ca/
COX-2 electrostatics with SC558
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
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