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

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

Oct 22, 2022 25 likes •370 views

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

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SLIDE 1

Computational Tools to Aid Modelling, Analysis, and Virtual Screening

Gaspar Pinto @ EJIBCE 2018

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SLIDE 2

▪ Who we are

Introduction

Brno Praha

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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SLIDE 3

▪ Enzymes with buried active site

Introduction

Computational Tools to Aid Modelling, Analysis and Virtual Screening

Haloalkane dehalogenase DhaA

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▪ Enzymes with buried active site… need tunnels

▪ Transport of substrates, products, solvent, cofactors ▪ Wide-spread features

  • 64% of known enzymes
  • All 6 enzyme classes

Introduction

Computational Tools to Aid Modelling, Analysis and Virtual Screening

Haloalkane dehalogenase DhaA

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▪ Protein tunnels: dynamic features

Introduction

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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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

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SLIDE 7

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

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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

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CAVER

▪ Dynamic tunnels

▪ Structure ensemble

Computational Tools to Aid Modelling, Analysis and Virtual Screening

identification of tunnels in each snapshot

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CAVER

▪ Dynamic tunnels

▪ Structure ensemble

Computational Tools to Aid Modelling, Analysis and Virtual Screening

identification of tunnels in each snapshot

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CAVER

▪ Dynamic tunnels

▪ Structure ensemble

Computational Tools to Aid Modelling, Analysis and Virtual Screening

identification of tunnels in each snapshot merging all identified tunnels

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CAVER

▪ Dynamic tunnels

▪ Structure ensemble ▪ Clustering of tunnels

Computational Tools to Aid Modelling, Analysis and Virtual Screening

identification of tunnels in each snapshot merging all identified tunnels clustering of tunnels

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CAVER

▪ Dynamic tunnels

▪ Analysis of tunnel dynamics ▪ Statistics, analysis and visualization output

Computational Tools to Aid Modelling, Analysis and Virtual Screening

clustering of tunnels analysis of tunnels tunnel dynamics

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SLIDE 14

Caver Analyst

▪ Graphical interface to CAVER

▪ User-friendly ▪ Static and dynamic structures ▪ Versatile representations

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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Caver Analyst

▪ Graphical interface to CAVER

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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SLIDE 16

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

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SLIDE 17

Caver Analyst

▪ Graphical interface to CAVER

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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SLIDE 18

Caver Analyst

▪ Graphical interface to CAVER

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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SLIDE 19

Caver Analyst

▪ Graphical interface to CAVER

Computational Tools to Aid Modelling, Analysis and Virtual Screening

time

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SLIDE 20

Caver Analyst – case study

DhaA80 DhaA106 DhaA

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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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

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SLIDE 22

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

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SLIDE 23

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

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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

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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

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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

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SLIDE 27

CaverDock – case study

Computational Tools to Aid Modelling, Analysis and Virtual Screening

DhaA DhaA31 (TCP) + Cl- (DCP)

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SLIDE 28

CaverDock – case study

Computational Tools to Aid Modelling, Analysis and Virtual Screening

DhaA DhaA31 (TCP) + Cl- (DCP)

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SLIDE 29

CaverDock – case study

Computational Tools to Aid Modelling, Analysis and Virtual Screening

DhaA DhaA31 (TCP) + Cl- (DCP)

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SLIDE 30

CaverDock – case study

Computational Tools to Aid Modelling, Analysis and Virtual Screening

DhaA DhaA31

  • 5
  • 3
  • 1

1 3 5 7 9 11 0,5 0,7 0,9 1,1 1,3 1,5 1,7 1,9 2,1 2,3 2,5 5 10 15 Energy [kcal/mol] Radius [Å] Tunnel length [Å]

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1 3 5 7 9 11 0,5 0,7 0,9 1,1 1,3 1,5 1,7 1,9 2,1 2,3 2,5 5 10 15 Energy [kcal/mol] Radius [Å] Tunnel length [Å]

(TCP) + Cl- (DCP)

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Virtual screening – Caver Analysis

Computational Tools to Aid Modelling, Analysis and Virtual Screening

Leukotriene A4

▪ Biosynthesis of a pro- inflammatory mediator ▪ Screening library: ▪ Anti-inflammatory agents ▪ 56 molecules ▪ 2 ligands discarded from the set

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Virtual screening – Data Analysis

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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Acknowledgements

Computational Tools to Aid Modelling, Analysis and Virtual Screening

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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