Analysis, and Virtual Screening Gaspar Pinto @ EJIBCE 2018 - PowerPoint PPT Presentation

Computational Tools to Aid Modelling, Analysis, and Virtual Screening Gaspar Pinto @ EJIBCE 2018

Introduction ▪ Who we are Praha Brno Computational Tools to Aid Modelling, Analysis and Virtual Screening

Introduction ▪ Enzymes with buried active site Haloalkane dehalogenase DhaA Computational Tools to Aid Modelling, Analysis and Virtual Screening

Introduction ▪ Enzymes with buried active site… need tunnels ▪ Transport of substrates, products, solvent, cofactors ▪ Wide-spread features - 64% of known enzymes - All 6 enzyme classes Haloalkane dehalogenase DhaA Computational Tools to Aid Modelling, Analysis and Virtual Screening

Introduction ▪ Protein tunnels: dynamic features Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Tool for tunnel computation ▪ Space characterization ▪ Voronoi diagrams ▪ Search for pathways ▪ Origin, probe radius, shell radius, clustering threshold Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Tool for tunnel computation ▪ Space characterization ▪ Voronoi diagrams ▪ Search for pathways ▪ Origin, probe radius, shell radius, clustering threshold Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Tool for tunnel computation ▪ Space characterization ▪ Voronoi diagrams ▪ Search for pathways ▪ Ranking of tunnels ▪ Based on bottleneck radius, length, curvature ▪ Command-line, PyMOL plugin Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Dynamic tunnels ▪ Structure ensemble identification of tunnels in each snapshot Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Dynamic tunnels ▪ Structure ensemble identification of tunnels in each snapshot Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Dynamic tunnels ▪ Structure ensemble identification of tunnels merging all identified in each snapshot tunnels Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Dynamic tunnels ▪ Structure ensemble ▪ Clustering of tunnels clustering of tunnels identification of tunnels merging all identified in each snapshot tunnels Computational Tools to Aid Modelling, Analysis and Virtual Screening

CAVER ▪ Dynamic tunnels ▪ Analysis of tunnel dynamics ▪ Statistics, analysis and visualization output clustering of tunnels analysis of tunnels tunnel dynamics Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER ▪ User-friendly ▪ Static and dynamic structures ▪ Versatile representations Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER ▪ User-friendly ▪ Static and dynamic structures ▪ Versatile representations ▪ Compute protein cavities Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Graphical interface to CAVER time Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst – case study DhaA DhaA80 DhaA106 Computational Tools to Aid Modelling, Analysis and Virtual Screening

Caver Analyst ▪ Caver Analyst 2.0 ▪ Improved tunnel analysis ▪ Mutagenesis ▪ Enhanced visualization ▪ Video recording ▪ Saving images with no background ▪ www.caver.cz Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock ▪ Tool to study ligand transport through tunnels ▪ Substrate, products, inhibitors ▪ Based on CAVER and AutoDock Vina ▪ Trajectory computation Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock ▪ Tool to study ligand transport through tunnels ▪ Substrate, products, inhibitors ▪ Based on CAVER and AutoDock Vina ▪ Lower-bound trajectory Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock ▪ Tool to study ligand transport through tunnels ▪ Substrate, products, inhibitors ▪ Based on CAVER and AutoDock Vina ▪ Continuous movement Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock ▪ Tool to study ligand transport through tunnels ▪ Substrate, products, inhibitors ▪ Based on CAVER and AutoDock Vina ▪ Optimized trajectory Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock ▪ Tool to study ligand transport through tunnels ▪ Substrate, products, inhibitors ▪ Based on CAVER and AutoDock Vina ▪ Flexibility can be added ▪ Trajectory and binding energy along tunnel Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock – case study DhaA DhaA31 (TCP) (DCP) + Cl - Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock – case study DhaA DhaA31 (TCP) (DCP) + Cl - Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock – case study DhaA DhaA31 (TCP) (DCP) + Cl - Computational Tools to Aid Modelling, Analysis and Virtual Screening

CaverDock – case study DhaA DhaA31 (TCP) (DCP) + Cl - 2,5 2,5 11 11 2,3 2,3 9 9 2,1 2,1 Energy [kcal/mol] Energy [kcal/mol] 1,9 7 7 1,9 Radius [Å] Radius [Å] 1,7 1,7 5 5 1,5 1,5 3 3 1,3 1,3 1 1 1,1 1,1 -1 -1 0,9 0,9 -3 -3 0,7 0,7 0,5 -5 0,5 -5 0 5 10 15 0 5 10 15 Tunnel length [Å] Tunnel length [Å] Computational Tools to Aid Modelling, Analysis and Virtual Screening

Virtual screening – Caver Analysis Leukotriene A4 Biosynthesis of a pro- ▪ inflammatory mediator Screening library: ▪ ▪ Anti-inflammatory agents ▪ 56 molecules ▪ 2 ligands discarded from the set Computational Tools to Aid Modelling, Analysis and Virtual Screening

Virtual screening – Data Analysis Computational Tools to Aid Modelling, Analysis and Virtual Screening

Acknowledgements Computational Tools to Aid Modelling, Analysis and Virtual Screening

Software tools by LL & Co. CAVER, Caver Analyst http://www.caver.cz FireProt http://loschmidt.chemi.muni.cz/fireprot Hotspot Wizard http://loschmidt.chemi.muni.cz/hotspotwizard Predict SNP http://loschmidt.chemi.muni.cz/predictsnp CalFitter http://https://loschmidt.chemi.muni.cz/calfitter Computational Tools to Aid Modelling, Analysis and Virtual Screening