A Path Planning Approach for Computing A Path Planning Approach for - PowerPoint PPT Presentation

A Path Planning Approach for Computing A Path Planning Approach for Computing Large- -Amplitude Motions of Flexible Molecules Amplitude Motions of Flexible Molecules Large Juan Cortés & Thierry Siméon MOVIE Workshop, Toulouse, 7-8/01/2005

Context : Computational Biology Context : Computational Biology ( Interaction ) Flexibility Bio-informatics Molecular modeling MOVIE Workshop, Toulouse, 7-8/01/2005

Protein Flexibility Protein Flexibility Loop motions vs. Strong QuickTime™ et un décompresseur Codec YUV420 sont requis pour visionner cette image. QuickTime™ et un décompresseur DV - PAL sont requis pour visionner cette image. Domain motions Side chains Low QuickTime™ et un décompresseur Codec YUV420 QuickTime™ et un sont requis pour visionner cette image. décompresseur Codec YUV420 sont requis pour visionner cette image. Plasticity vs. Global Local MOVIE Workshop, Toulouse, 7-8/01/2005

Difficulty : Complexity of Potential Energy Difficulty : Complexity of Potential Energy Stretching Bonded Bending terms Torsion Lennard Jones Non-bonded Electrostatic terms : H bonds, hydrophobic interactions ,… Other MOVIE Workshop, Toulouse, 7-8/01/2005

Potential Energy → Potential Energy Geometric Constraints Geometric Constraints → Stretching Bonded Bending terms Torsion Lennard Jones Non-bonded Electrostatic terms Other MOVIE Workshop, Toulouse, 7-8/01/2005

A Two- -Stage Approach Stage Approach A Two Filtering • Exploration under geometric constraints Motion planning algorithms • Energy-based exploration Classical molecular modeling methods New methods ? MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Collision Detection Geometric Tools : Collision Detection Challenge : Self-collisions of highly articulated mechanisms BioCD [Robotics’05 (submitted)] • Tailored for protein models • Dual structure (kd-trees) • first level • second level • Many d.o.f. change simultaneously • Performance: Hundreds of tests/second MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Conformational Sampling Geometric Tools : Conformational Sampling Kinematic loop closure → → RLG [ICRA’02] → → Mechanical system decomposition • active variables → q a → → → loop 2 active subchain(s) loop 3 • passive variables → → q p → → passive subchain loop 1 non-redundant mechanism - planar : 3 d.o.f. - spatial : 6 d.o.f. MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Conformational Sampling Geometric Tools : Conformational Sampling Kinematic loop closure → → RLG [ICRA’02] → → Passive variables ← Active variables ← ← guided sampling ← inverse kinematics ← ← ← ← MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Conformational Sampling Geometric Tools : Conformational Sampling Protein loop [J Comput Chem 04] • Main chain (backbone) rigid unit dihedral • Side chains angle begin end MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Conformational Sampling Geometric Tools : Conformational Sampling Protein loop [J Comput Chem 04] • Main chain (backbone) • active subchain RLG & BioCD • • passive subchain general 6 R IK + BioCD • rigid unit dihedral • Side chains angle random sampling + BioCD • begin end MOVIE Workshop, Toulouse, 7-8/01/2005

Geometric Tools : Conformational Exploration Geometric Tools : Conformational Exploration Incremental search → → RRT [LaValle and Kuffner, 2001] → → DD-RRT [ICRA’05] � Good performance in very constrained search space MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Analysis of Protein Loop Mobility Applications : Analysis of Protein Loop Mobility Xylanase Flexible loop : 69 d.o.f. from Thermobacillus xylanilyticus MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Analysis of Protein Loop Mobility Applications : Analysis of Protein Loop Mobility Conformational sampling Two-step simulated annealing → Several days of work Energetically feasible conformation Hydrogen bond network from geometrically feasible one → RMSD = 0.65 Å Geometric approach → Up to few minutes MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Analysis of Protein Loop Mobility Applications : Analysis of Protein Loop Mobility Conformational exploration Exploration with RRT • 5000 nodes • < 1 hour QuickTime™ et un décompresseur Codec YUV420 sont requis pour visionner cette image. Mutated Xylanase Xylanase (deletion 111, 121) from Thermobacillus xylanilyticus � Prediction for directed mutagenesis MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Ligand Applications : Ligand- -Protein Protein Accessibility Pathways Accessibility Pathways Prediction of enzymatic enantioselectivity R enantiomer Ligand and side-chain S enantiomer Bulkholderia cepacia Deep active site (17Å) flexibility : 45 d.o.f. Lipase MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Ligand Applications : Ligand- -Protein Protein Accessibility Pathways Accessibility Pathways Prediction of enzymatic enantioselectivity QuickTime™ et un QuickTime™ et un décompresseur DV - PAL décompresseur DV - PAL sont requis pour visionner cette image. sont requis pour visionner cette image. Ligand: ( S )-ph(Br)Et Ligand: ( R )-ph(Br)Et MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Ligand Applications : Ligand- -Protein Protein Accessibility Pathways Accessibility Pathways Correlation of results Pseudo-molecular dynamics Two-stage approach distance ( � ) distance ( � ) 4,5 5,5 6,5 7,5 8,5 9,5 10,5 4,5 5,5 6,5 7,5 8,5 9,5 10,5 -10 -10 -15 -15 -20 -20 -25 -25 -30 -30 -35 -35 R R -40 -40 S S energy-based approach two-stage approach Computing time = 3 days Computing time = 30 minutes (including energy minimization) � Similar trajectories and energetic profiles MOVIE Workshop, Toulouse, 7-8/01/2005

Applications : Ligand Applications : Ligand- -Protein Protein Accessibility Pathways Accessibility Pathways Correlation of results � Computing time ratio ~ enantioselectivity MOVIE Workshop, Toulouse, 7-8/01/2005

Future Work Future Work • Integrating loop motions in the analysis of interactions Ligand-protein Protein-protein • Automatic identification of flexible regions → Normal mode analysis MOVIE Workshop, Toulouse, 7-8/01/2005

A Path Planning Approach for Computing A Path Planning Approach for Computing Large- -Amplitude Motions of Flexible Molecules Amplitude Motions of Flexible Molecules Large Juan Cortés Thierry Siméon jcortes@laas.fr nic@laas.fr MOVIE Workshop, Toulouse, 7-8/01/2005

MOVIE Workshop, Toulouse, 7-8/01/2005