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