Inhalt

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   Acknowledgments
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   Abstract
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  1 Introduction
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   1.1 Modeling and Visualizing the cytological Cosmos
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   1.2 CELLmicrocosmos: A bidirectional Approach
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   1.3 CELLmicrocosmos: An interdisciplinary Approach
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  1.4 Project and Thesis Structure
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   1.4.1 Mesoscopic Level [MES]
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   1.4.2 Molecular Level [MOL]
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   1.4.3 Functional Level [FUN]
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   1.4.4 Integrative Level [MES+MOL+FUN]
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  2 Biological Background
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  2.1 [MES] Mesoscopic Composition
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   2.1.1 The Cell
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   2.1.2 Cell Types
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  2.1.3 Cell Components and their Substructures
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   2.1.3.1 Plasma membrane
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   2.1.3.2 Cell Walls
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   2.1.3.3 Cytosol
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   2.1.3.4 Nucleus
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   2.1.3.5 Nucleolus
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   2.1.3.6 Endoplasmic reticulum
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   2.1.3.7 Ribosome
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   2.1.3.8 Golgi apparatus
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   2.1.3.9 Peroxisome
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   2.1.3.10 Mitochondrion
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   2.1.3.11 Chloroplast
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   2.1.3.12 Vesicle
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   2.1.3.13 Endosome
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   2.1.3.14 Lysosome
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   2.1.3.15 Vacuole
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   2.1.3.16 Extracellular matrix
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   2.1.3.17 Volume of Cell Components
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  2.2 [MOL] Molecular Composition
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  2.2.1 The Molecules of Cells
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   2.2.1.1 Carbohydrates
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   2.2.1.2 Nucleic Acids
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   2.2.1.3 Lipids, van der Waals and covalent Forces
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   2.2.1.4 Amino Acids and Proteins
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   2.2.1.5 Small Molecules
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   2.2.2 Membrane Model History
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   2.2.3 The Fluid Mosaic Model
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   2.2.4 Proteins in Membranes
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   2.2.5 Microdomains and Rafts
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   2.2.6 Membrane Compositions
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  2.3 [FUN] Metabolism
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   2.3.1 Enzyme, Products and Substrates
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   2.3.2 The Gain of Energy for Reactions
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   2.3.3 Biological Energy: ATP
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   2.3.4 Metabolic Pathways and Energy
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   2.3.5 The Citrate Cycle
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   2.4 [MES+MOL+FUN] Integrative Cytology?
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  3 Technical Background
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  3.1 [MES] Cell Microscopy and Modeling
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   3.1.1 Microscopy Types
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   3.1.1.1 Light Microscopy
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   3.1.1.2 Electron Microscopy
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   3.1.1.3 Summary
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  3.1.2 Microscopy Databases
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   3.1.2.1 CCDB
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   3.1.2.2 EMDB
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  3.1.3 Cell Modeling and Simulation
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   3.1.3.1 Amira
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   3.1.3.2 3ds Max
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   3.1.3.3 Blender
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   3.1.3.4 The VRML-Format
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   3.1.3.5 Cell Simulation
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  3.2 [MOL] Membrane Modeling
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  3.2.1 Spectroscopy Types
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   3.2.1.1 X-Ray Crystallography
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   3.2.1.2 Electron Crystallography
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   3.2.1.3 Nuclear Magnetic Resonance (NMR) Spectroscopy
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   3.2.1.4 Summary
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  3.2.2 Structure Databases
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  3.2.2.1 Protein Databases
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   3.2.2.1.1 The Protein Data Bank (PDB): Database and Format
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   3.2.2.1.2 DisProt
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   3.2.2.1.3 Protein Modal Portal
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   3.2.2.1.4 PDBTM
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   3.2.2.1.5 OPM
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  3.2.2.2 Lipid Databases
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   3.2.2.2.1 HIC-UP
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   3.2.2.2.2 PDB Ligand Expo
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   3.2.2.2.3 Avanti Lipids
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   3.2.2.2.4 Klotho
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   3.2.2.2.5 Chemistry Molecular Models
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   3.2.2.3 Membrane Databases
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   3.2.2.4 Quantitative Comparison of Databases
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   3.2.3 Membrane Modeling and Simulation
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   3.2.4 Membrane Packing Problems
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  3.2.5 Traditional Membrane Modeling Methods
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   3.2.5.1 Replacement Methods
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   3.2.5.2 Insertion Methods
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   3.2.5.3 Discussion
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   3.2.6 The Knapsack Problem
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   3.2.7 Packing Densities as a qualitative Criterion
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  3.3 [FUN] Network Reconstruction and Localization
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   3.3.1 Experimental Methods
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   3.3.2 Pathway and Localization Databases
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  3.3.2.1 Pathway Databases
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   3.3.2.1.1 KEGG
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   3.3.2.1.2 Reactome
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  3.3.2.2 Localization Databases
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   3.3.2.2.1 Reactome
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   3.3.2.2.2 BRENDA and the Enzyme Classification
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   3.3.2.2.3 UniProt
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   3.3.2.2.4 The Gene Ontology and the Redundancy of Terms
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   3.3.2.2.5 SUBA
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   3.3.3 Data Integration
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   3.3.3.1 The Data Warehouse: BioDWH and DAWIS-M.D.
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   3.3.3.2 ANDCell/ANDVisio
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  3.3.4 Network Mapping Problem
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   3.3.4.1 Node Distribution Problem
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   3.3.4.2 Network Layout Problem
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   3.3.4.3 Node Mapping Problem
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   3.4 [MES+MOL+FUN] Summary
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   3.4.1 Overview of Levels
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   3.4.2 Overview of Databases
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  3.4.3 Programming Tools
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   3.4.3.1 Java
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   3.4.3.2 Java 3D
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  4 Related Approaches
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  4.1 [MES] Cell Modeling Tools
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  4.1.1 Visual Cell Modeling
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   4.1.1.1 CELLmicrocosmos 1.0 DisplayCell
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   4.1.1.2 Meta!Blast
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   4.1.1.3 The Visible Cell® Project
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   4.1.1.4 AutoFill/AutoCell
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   4.1.1.5 LifeExplorer
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   4.1.2 Mathematical Cell Modeling and Simulation
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   4.1.2.1 E-Cell
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   4.1.2.2 The Virtual Cell (VCell)
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   4.1.2.3 CompuCell3D
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   4.1.2.4 ENVIRONMENT
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   4.1.3 Summary
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  4.2 [MOL] Membrane Modeling Tools
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   4.2.1 Membrane Visualization
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   4.2.2 Membrane Modeling
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   4.2.2.1 A Grid-based Method using MOE
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   4.2.2.2 ChemSW® Chemsite Pro®
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   4.2.2.3 CHARMM-GUI Membrane Builder
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   4.2.2.4 VMD Membrane-Plugin
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   4.2.2.5 Packmol
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   4.2.3 Summary
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  4.3 [FUN] Network Modeling Tools
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  4.3.1 2D Network Modeling Tools
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   4.3.1.1 Cytoscape
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   4.3.1.2 VANTED
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   4.3.1.3 VANESA
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  4.3.2 2.5D Network Modeling Tools
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   4.3.2.1 2.5D Network Comparison
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   4.3.2.2 Arena3D
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   4.3.2.3 BioCichlid
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  4.3.3 3D Network Modeling Tools
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   4.3.3.1 Metabolic Pathways in VRML
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   4.3.3.2 MetNetVR
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   4.3.3.3 GEOMI: Protein Interaction Networks in 3D
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   4.3.3.4 The Interactorium
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   4.3.3.5 Integration and Visualization of Multimodal Biological Data
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   4.3.3.6 3DScape
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   4.3.4 Summary
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   4.4 [MES+MOL+FUN] The missing Link
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   5 Methods and Implementation
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  5.1 [MES] Mesoscopic Modeling: Constructing a Virtual Cell Environment
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  5.1.1 Requirements
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   R1.I Realistic Cell Component Models (Abstraction Level 1)
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   R1.II Interpretative Cell Component Models (Abstraction Level 2)
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   R1.III Abstract Cell Component Models (Abstraction Level 3)
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   R1.IV Multiple Cell Component Types
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   R1.V Cell Component Layers
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   R1.VI Multiple Cell Compositions
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   R1.VII Cell Component Distribution
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   R1.VIII Color Schemes
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   R1.IX Import Capabilities
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   R1.X Export Capabilities
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   5.1.2 Methods
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   5.1.2.1 Cell Component Modeling and Abstraction Levels
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   5.1.2.1.1 3D-microscopy-based Modeling (Abstraction Level 1)
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   5.1.2.1.2 Molecular-structure-based Cell Component Modeling (Abstraction Level 1)
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   5.1.2.1.3 Interpretative Cell Component Modeling (Abstraction Level 2)
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   5.1.2.1.4 Abstract Cell Component Modeling (Abstraction Level 3)
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   5.1.2.2 Cell components in CellEditor and the SphereCell
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   5.1.2.3 Coloring Methods for Cell Components
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   5.1.2.3.1 Contrast Color Codes
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   5.1.2.3.2 Color Scales
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   5.1.2.3.3 The Color Codes/Scales in CellEditor
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   5.1.2.4 Cell Component Layers
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   5.1.2.5 CellEditor
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   5.1.2.6 Placing cell models
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   5.1.2.7 Import and Export Capabilities
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   5.1.3 Implementation Details
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  5.2 [MOL] Molecular Modeling: Integrating Lipids and Proteins into a Membrane
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  5.2.1 Requirements
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   R2.I Compatibility with different molecule types
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   R2.II Compatibility with the Fluid Mosaic Model
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   R2.III Membrane Composing
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   R2.IV Incorporation of microdomains
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   R2.V Performance for Desktop PCs and Laptop PCs
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   R2.VI Solution to Membrane Packing Problems
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   R2.VII Restriction to Geometrical Problem Solving
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   R2.VIII Semi-automatic Placement of Proteins
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   R2.IX Access to Databases: PDB, PDBTM and OPM
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   R2.X Visualization
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   R2.XI Packing Quality Verification
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   R2.XII Export capabilities for further visualizations and simulations
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   R2.XIII Import capabilities to analyze and visualize externally modified membranes
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   R2.XIV Modularity
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   R2.XV Reproducibility
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  5.2.2 Methods
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   5.2.2.1 PDB Integration
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  5.2.2.2 Lipid and Protein Packing
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   5.2.2.2.1 Lipid Packing
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   5.2.2.2.2 Protein Packing
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   5.2.2.2.3 Membrane Packing
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   5.2.2.3 Shape-based and Atomic-based Computation and Visualization
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   5.2.2.4 Membrane Model: Stacks and Microdomains
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   5.2.2.5 Lipid Packing Algorithms and the Two-and-a-half-dimensional Knapsack Problem
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   5.2.2.6 A high-density-generating Plugin Algorithm: The Wanderer
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   5.2.2.7 The Plugin-Interface
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   5.2.2.8 Seed-based random number generation
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   5.2.2.9 Reverse-Parsing
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   5.2.2.10 Lipid Packing Density and Statistics
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   5.2.3 Implementation Details
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  5.3 [FUN] Functional Modeling: Integrating Metabolic Networks into a Virtual Cell
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  5.3.1 Requirements
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   R3.I Import of Cell Models
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   R3.II Access to a Data Warehouse
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   R3.III Import of Network Structures
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   R3.IV Differentiation of Localization Terms
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   R3.V Import of Localization Data
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   R3.VI Access to Localization References
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   R3.VII Localization Visualization
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   R3.VIII Combination of different Networks
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   R3.IX Coloring Methods for the Network
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   R3.X Coloring Methods for the Localizations
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   R3.XI Node Distribution Algorithms
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   R3.XII Node Mapping Functions
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   R3.XIII Interactivity
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   R3.XIV 3D Navigation
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   R3.XV Shading for the Network
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   R3.XVI 3D Stereoscopy
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   R3.XVII Desktop and VR-ready
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   R3.XVIII Reproducibility
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  5.3.2 Methods
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   5.3.2.1 Cell Modeling as Basis
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  5.3.2.2 Network Reconstruction
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   5.3.2.2.1 Metabolic Pathways from KEGG
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   5.3.2.2.2 Pathway Import via SBML/AND
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   5.3.2.2.3 2D Viewer
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  5.3.2.3 Protein Localization
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   5.3.2.3.1 The Databases
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   5.3.2.3.2 Localization Import via AND
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   5.3.2.3.3 The Mapping Table
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   5.3.2.3.4 The Localization Table and Localization Referencing
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   5.3.2.3.5 The Localization Charts
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   5.3.2.4 Correlating Networks with Cell Components
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  5.3.2.5 Network Layouts
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   5.3.2.5.1 UUUSphere
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   5.3.2.5.2 ISOM
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   5.3.2.6 Node Mapping
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   5.3.2.7 Correlating Networks
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   5.3.2.8 Coloring Methods for Networks
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   5.3.2.9 Coloring Methods for Nodes
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   5.3.2.10 CELLmicrocosmos Navigation and the NodeDetails Window
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   5.3.2.11 3D Stereoscopy and Shading
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  5.3.2.12 Export Capabilities
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   5.3.2.12.1 XML (.Cm4)
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   5.3.2.12.2 SBML
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   5.3.2.12.3 VRML97
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   5.3.3 Implementation Details
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   5.3.3.1 Integration of DAWIS-M.D. and ANDCell
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  5.4 [MES+MOL+FUN] Integrative Modeling: Combining Mesoscopic, Molecular and Functional Modeling
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  5.4.1 Requirements
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   R4.I Combination of CellExplorer and MembraneEditor
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   R4.II Membrane Mapping
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  5.4.2 Methods
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   5.4.2.1 CellExplorer
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   5.4.2.2 CmX mRNA
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   5.4.2.3 Membrane Mapping
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   5.4.3 Implementation Details
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  6 Application Cases
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  6.1 [MES] Cm3 CellEditor
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  6.1.1 Construction of an Animal Cell
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   6.1.1.1 Construction of an Animal Comparison Cell
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   6.1.1.2 Construction of a regular Animal Cell
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   6.1.2 Construction of a Plant Cell
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   6.1.3 Construction of a Bacterial Cell
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   6.1.4 Construction of a SphereCell
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   6.1.5 VRML import of single cell components
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   6.1.6 VRML export of the whole cell environment
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   6.1.7 Cell Models for Exhibitions
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   6.1.8 Cell Models for Education
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  6.2 [MOL] Cm2 MembraneEditor
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   6.2.1 Modeling of inner and outer mitochondrial membranes
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   6.2.1.1 Modeling an outer mitochondrial membrane
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   6.2.1.2 Incorporation of cholesterol
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   6.2.1.3 Addition of an inner mitochondrial membrane
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   6.2.2 Application to the Classical 2D-Knapsack-Problem
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   6.2.3 Protein Placement
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   6.2.4 Computation of extreme densities
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   6.2.5 Modeling of a lipid raft-containing plasma membrane
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  6.3 [FUN] Cm4 PathwayIntegration
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  6.3.1 Localizing metabolic Pathways
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   6.3.1.1 Downloading the Citrate Cycle and the Glycolysis
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   6.3.1.2 First Localization Results
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   6.3.1.3 Investigating the preliminary Localizations
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   6.3.1.4 Examining an Outsider by direct Access to external Sources
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   6.3.1.5 Localization Result
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   6.3.1.6 3D Visualization
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  6.3.2 Cytological Disease Mapping
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   6.3.2.1 The Protein-Protein-Interaction Network Reconstruction
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   6.3.2.2 First Localization Results
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   6.3.2.3 Localization Assignment of the Pathway
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   6.3.2.4 Inter-species Comparison of three Pathways
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   6.3.2.5 Proof of Concept
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  6.4 [MES+MOL+FUN] Cm1 CellExplorer and CmX mRNA
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   6.4.1 Integrative Cell Models for Visualization
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   6.4.2 An interactive Journey from the Mesoscopic to the Molecular Level
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   6.4.3 An Animal Cell associated with publication-based Membranes
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  7 Conclusions and Outlook
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   7.1 [MES] Cell Modeling at the Mesoscopic Level
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   7.2 [MOL] Cell Modeling at the Molecular Level
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   7.3 [FUN] Cell Modeling at the Functional Level
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   7.4 [MES+MOL+FUN] Integrative Cell Modeling
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   7.5 Synthetic Cell Modeling
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   8 References
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  9 Appendix
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  9.1 Biological Abbreviations
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  9.1.1 Lipid Abbreviations [Genn89]
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  9.1.1.1 (Glycero-)Phospholipids
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   9.1.1.1.1 Cardiolipin
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   9.1.1.1.2 Phosphatidic Acid
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   9.1.1.1.3 Phosphatidylcholine
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  9.1.1.2 Phosphatidylethanolamine
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   9.1.1.2.1 Phosphatidylglycerol
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   9.1.1.2.2 Phosphatidylinositol
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   9.1.1.2.3 Phosphatidylserine
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  9.1.1.3 Sphingolipids
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   9.1.1.3.1 Sphingomyelin
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  9.1.1.4 Sterols
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   9.1.1.4.1 Cholesterol
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   9.1.2 Other Biological Abbreviations
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   9.2 Technical Abbreviations
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   9.3 Optimization Problem Definition
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   9.4 Abstraction Levels
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   9.5 Special Terms
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   9.6 The PDB Format: An Example
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   9.7 A Simple Membrane Packing Algorithm
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   9.8 The Enzyme Classification: An Example
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   9.9 2D Visualization of the Glycolysis in the 2D Viewer of CmPI
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   9.10 Coordinate Axes
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   9.11 Units and molecular components
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   9.12 Units of the cell
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   9.13 Common names of fatty acids
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   9.14 The Color Codes derived from the Color Alphabet of Green-Armytage
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   9.14.1 Color Codes for Eukayotic Cell Components
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   9.14.2 Color Codes for Prokaroytic Cell Components
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   9.15 Versioning Information
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   9.16 Projects and Participants
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   9.17 Implementation Work
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   9.17.1 Implementation Work of Björn Sommer
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   9.17.2 Implementation Work of Students and Colleagues
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   9.17.3 Cell Components and their Authors
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   9.18 Used Programs
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  9.19 Complete Comparison Tables
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   9.19.1 Cell Modeling Tools
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   9.19.2 Membrane Modeling Tools
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   9.19.3 Network Modeling Tools