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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.
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Contents of the presentation
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Next generation grid technology
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Configurable interaction force fields
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Force field visualisation techniques
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Results on
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Trypsin - APPA
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Ras P21 - GDP
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COX2 - SC558
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Grid resolution problem
1.6Å
1.0Å
0.5Å
0.16Å
7K points
30K points
250K points
7300K points
0.3 MB
1.3 MB
11 MB
321 MB
0.22 min
1 min
8 min
216 min
50% error
20%error
8% error
2% error
SimBioSys Inc.© 2001
http://www.simbiosys.ca/
Variable resolution grids
0.15Å-3.0Å variable
28K points
1.5 MB
1 min
2%
http://www.simbiosys.ca/
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Grid spacing 0.15Å-3.0Å
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Memory and CPU (build)
~1Å-1.5Å grid equivalent
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Precision for ligand atoms
~0.15Å grid equivalent
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Octree, hashing
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Hierarchical grid:
constant access time
SimBioSys Inc.© 2001
Interaction Force Fields 1.
Lp
http://www.simbiosys.ca/
-
O
C
Lp
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Van der Waals: Lennard Jones
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Electrostatics: Coulomb
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Parameters based on AMBER
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Partial charges of H-bond
acceptors are distributed to the
lone pairs at 1Å distance from the
heavy atom
SimBioSys Inc.© 2001
Interaction Force Fields 2.
Hydrogen bond term:
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A
Lp
H
D
http://www.simbiosys.ca/
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A-H and D-Lp distances
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Proton directionality: cos2(D-H-A)
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Lone pair directionality: cos(A-Lp-H)
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Optimum directionality vectors
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Multiple receptor atom effects
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Separate donor, acceptor grids
SimBioSys Inc.© 2001
Interaction Force Fields 3.
Hydrophobicity term:
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Distance dependent functions (e.g. Lennard-Jones)
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Polar repulsion component
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Clash penalty component
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Activity flags (assigned using knowledge base)
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Highly configurable setup
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Smooth functions
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Force field visualization
techniques
• 2D surfaces
• Molecular surface map
• Contour iso-surface
• Color coded cut plane
http://www.simbiosys.ca/
• True 3D visualisation
• Volume rendering
SimBioSys Inc.© 2001
APPA electro and H-bond fields
with Volume Rendering
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
http://www.simbiosys.ca/
APPA H-bond donor field
visualisations
SimBioSys Inc.© 2001
Trypsin forces compared to APPA
atoms
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Ras P21H-bond acceptor field with
GDP
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Ras P21 H-bond donor field with
GDP
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Ras P21 electrostatic and H-bond fields
compared to GDP ligand atoms
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
COX- 2 hydrophobicity field with
SC558
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
COX-2 electrostatics with SC558
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Conclusion
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"No compromise" solution to eliminate the well
known grid resolution problem
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Force Field validation - looking for collaborators
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Volume rendering is "The Ultimate" solution for
3D force field visualisation
- now available with interactive speed on
cheap PC hardware
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The “InterView” software
http://www.simbiosys.ca/
SimBioSys Inc.© 2001
Acknowledgements
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Timur Skeini, Irina and Zsolt Szabo
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Peter Johnson & ICAMS - consultations
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Linux community - development platform
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nVidia, ATI etc. - fast volume rendering
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The organizers - opportunity
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The audience - attention and patience
http://www.simbiosys.ca/
SimBioSys Inc.© 2001