Molecular Conceptor 2 - Table of Contents
pdf version (350 KB)
The Molecular Conceptor course addresses a range fields including Medicinal Chemistry, Cheminformatics, Structural Bioinformatics and Drug Design.
If you would like to know which chapters in Molecular Conceptor relate to each of these fields, then click on the corresponding field:
Medicinal Chemistry
- A5. Conformational Analysis
- A6. Selected Examples in 3D Analysis
- A7. Molecular Graphics
- B2. Protein Structure
- B4. Molecular Docking
- B6. Molecular Dynamics
- C1. Introduction to Drug Discovery (in the pipeline)
- C2. Principles of Rational Drug Design
- C3. Structure Activity Relationships
- C5. Success Stories in Drug Discovery (in progress)
- C6. Examples of Scaffold Morphing
- D1. Structure-Based Drug Design: Analysis
- D2. Structure-Based Drug Design: Design
- D3. Structure-Based Drug Design: Examples
- E1. Pharmacophore-Based Drug Design: Analysis
- E2. Pharmacophore-Based Drug Design: Design
- E3. Pharmacophore-Based Drug Design: Examples
- F1. QSAR Principles and Methods
- F2. 3D-QSAR
- G1. Synthesis of Drugs
- G2. Library Design
- H1. Peptidomimetics
- H2. Peptidomimetics Examples
- I1. ADME Properties
- J1. Cheminformatics, Principles and Applications (in progress)
- J3. 3D Database Searching
- J4. Examples of 3D Database Searching
- J5. Molecular Similarity
Cheminformatics
- A1. Molecular Geometry
- A2. Molecular Properties
- A3. Stereochemistry
- A4. Molecular Energies
- A5. Conformational Analysis
- A6. Selected Examples in 3D Analysis
- A7. Molecular Graphics
- C1. Introduction to Drug Discovery (in the pipeline)
- C2. Principles of Rational Drug Design
- C3. Structure Activity Relationships
- C5. Success Stories in Drug Discovery (in progress)
- C6. Examples of Scaffold Morphing
- D3. Structure-Based Drug Design: Examples
- E3. Pharmacophore-Based Drug Design: Examples
- F1. QSAR Principles and Methods
- F2. 3D-QSAR
- G1. Synthesis of Drugs
- G2. Library Design
- H1. Peptidomimetics
- H2. Peptidomimetics Examples
- I1. ADME Properties
- J1. Cheminformatics, Principles and Applications (in progress)
- J3. 3D Database Searching
- J4. Examples of 3D Database Searching
- J5. Molecular Similarity
Structural Bioinformatics
- B1. Structural Bioinformatics (in progress)
- B2. Protein Structure
- B4. Molecular Docking
- B6. Molecular Dynamics
- D1. Structure-Based Drug Design: Analysis
- D2. Structure-Based Drug Design: Design
- D3. Structure-Based Drug Design: Examples
Drug Design
- C1. Introduction to Drug Discovery (in the pipeline)
- C2. Principles of Rational Drug Design
- C3. Structure Activity Relationships
- C5. Success Stories in Drug Discovery (in progress)
- C6. Examples of Scaffold Morphing
- D1. Structure-Based Drug Design: Analysis
- D2. Structure-Based Drug Design: Design
- D3. Structure-Based Drug Design: Examples
- E1. Pharmacophore-Based Drug Design: Analysis
- E2. Pharmacophore-Based Drug Design: Design
- E3. Pharmacophore-Based Drug Design: Examples
- F1. QSAR Principles and Methods
- F2. 3D-QSAR
- H1. Peptidomimetics
- H2. Peptidomimetics Examples
- I1. ADME Properties
- J1. Cheminformatics, Principles and Applications (in progress)
- J3. 3D Database Searching
- J4. Examples of 3D Database Searching
- J5. Molecular Similarity
Full Table of Contents
A - MOLECULAR MODELING
- Molecular Geometry
- Molecular Properties
- Stereochemistry
- Molecular Energies
- Conformational Analysis
- Selected Examples in 3D Analysis
- Molecular Graphics
- Structural Bioinformatics (in progress) (*)
- Protein Structure
- Homology Modeling (in the pipeline)
- Molecular Docking
- Case Studies in Molecular Docking (in the pipeline)
- Molecular Dynamics
- Introduction to Drug Discovery (in the pipeline)
- Principles of Rational Drug Design
- Structure Activity Relationships
- Bioisosterism
- Success Stories in Drug Discovery (in progress) (*)
- Examples of Scaffold Morphing (*)
- Structure-Based Drug Design: Analysis
- Structure-Based Drug Design: Design
- Structure-Based Drug Design: Examples
- Pharmacophore-Based Drug Design: Analysis
- Pharmacophore-Based Drug Design: Design
- Pharmacophore-Based Drug Design: Examples
- Cheminformatics, Principles and Applications (in progress) (*)
- Encoding Molecules (in the pipeline)
- 3D Database Searching
- Examples of 3D Database Searching
- Molecular Similarity
(*) New: Released on Version 2.11
- A. MOLECULAR MODELING
- A1. MOLECULAR GEOMETRY
- A1.1. 2D/3D
- A1.1.1 Molecules Considered as 2D Structures
- A1.1.2 The Three-Dimensional Shape of a Molecule
- A1.1.3 2D and 3D Representations
- A1.1.4 A Molecule: An Assembly of Atoms in 3D
- A1.1.5 Molecular Lego
- A1.1.6 Molecular Fragments for Constructing Molecules
- A1.2. Conformers
- A1.2.1 A Molecule is a Flexible Entity
- A1.2.2 Conformation Definition
- A1.2.3 Example of Conformations of a Molecule
- A1.2.4 Bioactive Conformation
- A1.3. Torsion Angles
- A1.3.1 Interconversion Between Conformers
- A1.3.2 How Do Interconversions Occur?
- A1.3.3 Definition of the Conformers of a Molecule
- A1.3.4 The Torsion Angle Concept
- A1.3.5 Definition of Torsion Angles
- A1.3.6 Monitoring Torsion Angles
- A1.3.7 Newman Projections and Torsion Angles
- A1.3.8 Convention for the Sign of Torsion Angles
- A1.3.9 Ring Conformations
- A1.4. Conformational Complexity
- A1.4.1 Rigid and Flexible Molecules
- A1.4.2 Codeine and Fenoxedil
- A1.4.3 Monitoring Torsion Angle Combinations
- A1.4.4 Conformational Explosion
- A1.5. Ratio of Conformers
- A1.5.1 Mixtures of Conformers
- A1.5.2 Ratio of Conformers and Population
- A1.6. CHAPTER QUIZZES (Available only in Teaching Package)
- A1.6.1 Quiz 1
- A1.6.2 Quiz 2
- A1.6.3 Quiz 3
- A1.6.4 Quiz 4
- A1.6.5 Quiz 5
- A1.6.6 Quiz 6
- A1.6.7 Quiz 7
- A1.6.8 Quiz 8
- A1.6.9 Quiz 9
- A1.6.10 Quiz 10
- A1.6.11 Quiz 11
- A1.6.12 Quiz 12
- A1.6.13 Quiz 13
- A1.6.14 Quiz 14
- A1.6.15 Quiz 15
- A1.6.16 Quiz 16
- A1.6.17 Quiz 17
- A1.6.18 Quiz 18
- A1.6.19 Quiz 19
- A1.6.20 Quiz 20
- A1.6.21 Quiz 21
- A2. MOLECULAR PROPERTIES
- A2.1. Introduction
- A2.1.1 Properties of a Molecule
- A2.1.2 Average of a Conformational-Dependent Property
- A2.1.3 Importance of the 3D Molecular Geometries
- A2.2. Biological Properties
- A2.2.1 Biological Properties of Proteins
- A2.2.2 Biological Properties of Chiral Analgesics
- A2.3. Physical Properties
- A2.3.1 Physical Properties
- A2.3.2 Calculation of Other Physical Properties
- A2.4. Chemical Properties
- A2.4.1 Chemical Properties
- A2.4.2 Enolization of Keto-3 Steroids
- A2.4.3 Relative Stability of Isomers
- A2.4.4 Reactivity of Alkyl Halides
- A2.4.5 SN2 Mechanism
- A2.4.6 E2 Elimination Mechanism
- A2.4.7 Molecular Geometries and Chemical Properties
- A2.5. Many Properties
- A2.5.1 Many Properties of a Molecule
- A2.6. CHAPTER QUIZZES (Available only in Teaching Package)
- A2.6.1 Quiz 1
- A2.6.2 Quiz 2
- A2.6.3 Quiz 3
- A2.6.4 Quiz 4
- A2.6.5 Quiz 5
- A2.6.6 Quiz 6
- A2.6.7 Quiz 7
- A3. STEREOCHEMISTRY
- A3.1. Introduction
- A3.1.1 Introduction on Stereochemistry
- A3.1.2 Bond Lengths
- A3.1.3 Bond Multiplicity
- A3.1.4 Atom Size
- A3.1.5 Electronegativity
- A3.1.6 Hybridization
- A3.1.7 Bond Angles
- A3.1.8 Thorpe-Ingold Effect
- A3.1.9 Torsion Angles
- A3.1.10 Torsion Angle Sign Convention
- A3.1.11 Examples of Torsion Angles
- A3.1.12 Torsion Angle Descriptor (sp3-sp3)
- A3.1.13 Torsion Angle Descriptor (sp2-sp3)
- A3.2. Chirality
- A3.2.1 Chirality
- A3.2.2 Example 1
- A3.2.3 Example 2
- A3.2.4 Chirality Descriptor: Optical Rotation
- A3.2.5 Chirality Nomenclature
- A3.2.6 The Order of Priority
- A3.2.7 Examples of R/S Assignments
- A3.2.8 The Newman Projection
- A3.2.9 The Fischer Projection
- A3.2.10 Chirality: D/L
- A3.2.11 D-alanine
- A3.2.12 L-alanine
- A3.2.13 Chirality: Erythro/Threo
- A3.2.14 Threo
- A3.2.15 Erythro
- A3.2.16 Other Examples of Chiral Molecules
- A3.3. Double Bonds
- A3.3.1 Cis-Trans Stereochemistry of Double Bonds
- A3.3.2 E/Z Stereochemistry of Double Bonds
- A3.3.3 s-cis/s-trans Conformations
- A3.3.4 Re/Si Nomenclature of the Faces of Double Bonds
- A3.4. Rings
- A3.4.1 Rings
- A3.4.2 Chair
- A3.4.3 Boat
- A3.4.4 Twist Boat
- A3.4.5 Crown
- A3.4.6 Rings: Axial and Equatorial Orientations
- A3.5. Symmetry
- A3.5.1 Introduction on Symmetry Operations
- A3.5.2 Symmetry C2
- A3.5.3 Symmetry C3
- A3.5.4 Symmetry Sigma
- A3.5.5 Inversion (i)
- A3.5.6 Example of Inversion
- A3.5.7 Rotatory Reflection (Sn)
- A3.6. CHAPTER QUIZZES (Available only in Teaching Package)
- A3.6.1 Quiz 1
- A3.6.2 Quiz 2
- A3.6.3 Quiz 3
- A3.6.4 Quiz 4
- A3.6.5 Quiz 5
- A3.6.6 Quiz 6
- A3.6.7 Quiz 7
- A3.6.8 Quiz 8
- A3.6.9 Quiz 9
- A3.6.10 Quiz 10
- A3.6.11 Quiz 11
- A3.6.12 Quiz 12
- A3.6.13 Quiz 13
- A3.6.14 Quiz 14
- A3.6.15 Quiz 15
- A3.6.16 Quiz 16
- A3.6.17 Quiz 17
- A3.6.18 Quiz 18
- A3.6.19 Quiz 19
- A3.6.20 Quiz 20
- A3.6.21 Quiz 21
- A3.6.22 Quiz 22
- A3.6.23 Quiz 23
- A3.6.24 Quiz 24
- A3.6.25 Quiz 25
- A3.6.26 Quiz 26
- A3.6.27 Quiz 27
- A3.6.28 Quiz 28
- A3.6.29 Quiz 29
- A3.6.30 Quiz 30
- A4. MOLECULAR ENERGIES
- A4.1. Introduction
- A4.1.1 Internal Energy of a Molecule
- A4.1.2 Internal Energy Associated to a Conformation
- A4.1.3 Transition State
- A4.1.4 Potential Surface
- A4.1.5 Thermodynamics & Kinetics
- A4.2. Thermodynamics
- A4.2.1 Thermodynamics: Conformer Populations
- A4.2.2 Thermodynamics: Boltzmann Equation
- A4.2.3 Boltzmann Population Analysis for Two Conformers
- A4.2.4 Boltzmann Population Analysis for 3 Conformers
- A4.2.5 Thermodynamics: Cyclohexane Example
- A4.2.6 Thermodynamics: Methylcyclohexane Example
- A4.3. Kinetics
- A4.3.1 Kinetics
- A4.3.2 Kinetics: Arrhenius Equation
- A4.3.3 Kinetics: Arrhenius Graph
- A4.3.4 Kinetics Ethane Example
- A4.3.5 Kinetics Cyclohexane Example
- A4.3.6 Kinetics Amide Bond Example
- A4.4. Molecular Modeling
- A4.4.1 Molecular Modeling
- A4.4.2 Example of Kinetic or Thermodynamic Control
- A4.4.3 Lowering the Energy of the Transition State
- A4.4.4 Raising the Energy of the Transition State
- A4.4.5 Modifying Conformers Populations
- A4.4.6 Molecular Energies: The Key of Molecular Modeling
- A4.5. Modeling in Drug Design
- A4.5.1 Molecular Modeling in Drug Design
- A4.5.2 Importance of Energies: the Morphinan Example
- A4.5.3 Morphinan and D-nor Morphinan Alignment
- A4.5.4 Conformational Analysis of Morphinan
- A4.5.5 Conformational Analysis of D-nor Morphinan
- A4.5.6 A Rationale for Explaining the Activities Observed
- A4.5.7 Morphinan: Validation and Design
- A4.5.8 Preferred Conformer of Active Enantiomer
- A4.5.9 Preferred Conformer of Inactive Enantiomer
- A4.5.10 Restoring Activities to the Inactive Analog?
- A4.5.11 Morphinan Browser
- A4.5.12 What We Can Learn From The Morphinan Example
- A4.6. How to Calculate Energies
- A4.6.1 The Need of Tools for Calculating Energies
- A4.6.2 Two Methods for Calculating Energies
- A4.7. Quantum Mechanics
- A4.7.1 Calculation of Energies by the Schrodinger Equation
- A4.7.2 Ab-Initio and Semi-empirical Calculations
- A4.7.3 Calculation of Energies
- A4.7.4 The Density Function Theory
- A4.7.5 The Choice of a Method
- A4.8. Molecular Mechanics
- A4.8.1 Molecular Mechanics
- A4.8.2 Force-Field
- A4.8.3 Force Field Components
- A4.8.4 Bond Lengths: Stretching Contributions
- A4.8.5 Function
- A4.8.6 Examples of Elementary Stretching Contributions
- A4.8.7 Bond Angles: Bending Contributions
- A4.8.8 Function
- A4.8.9 Examples of Elementary Bending Contributions
- A4.8.10 Torsion Angles: Torsional Contributions
- A4.8.11 Function
- A4.8.12 Examples of Elementary Torsional Contributions
- A4.8.13 Van der Waals Interactions
- A4.8.14 Function
- A4.8.15 Examples of Elementary Van der Waals
- A4.8.16 Electrostatic Dipolar Contributions
- A4.8.17 Function
- A4.8.18 Examples of Elementary Electrostatic Contributions
- A4.8.19 Hydrogen Bond Energy Contributions
- A4.8.20 Function
- A4.8.21 Examples of Elementary Hydrogen Bond Contributions
- A4.8.22 Total Energy in a Force Field Calculation
- A4.8.23 Main Force Fields
- A4.8.24 What One Should Remember
- A4.8.25 Relative Energies
- A4.9. CHAPTER QUIZZES (Available only in Teaching Package)
- A4.9.1 Quiz 1
- A4.9.2 Quiz 2
- A4.9.3 Quiz 3
- A4.9.4 Quiz 4
- A4.9.5 Quiz 5
- A4.9.6 Quiz 6
- A4.9.7 Quiz 7
- A4.9.8 Quiz 8
- A4.9.9 Quiz 9
- A4.9.10 Quiz 10
- A4.9.11 Quiz 11
- A4.9.12 Quiz 12
- A4.9.13 Quiz 13
- A4.9.14 Quiz 14
- A4.9.15 Quiz 15
- A4.9.16 Quiz 16
- A4.9.17 Quiz 17
- A4.9.18 Quiz 18
- A4.9.19 Quiz 19
- A4.9.20 Quiz 20
- A4.9.21 Quiz 21
- A4.9.22 Quiz 22
- A4.9.23 Quiz 23
- A4.9.24 Quiz 24
- A4.9.25 Quiz 25
- A4.9.26 Quiz 26
- A4.9.27 Quiz 27
- A4.9.28 Quiz 28
- A4.9.29 Quiz 29
- A4.9.30 Quiz 30
- A4.9.31 Quiz 31
- A4.9.32 Quiz 32
- A4.9.33 Quiz 33
- A4.9.34 Quiz 34
- A4.9.35 Quiz 35
- A4.9.36 Quiz 36
- A4.9.37 Quiz 37
- A4.9.38 Quiz 38
- A4.9.39 Quiz 39
- A4.9.40 Quiz 40
- A5. CONFORMATIONAL ANALYSIS
- A5.1. Introduction
- A5.1.1 Geometries, Energies and Conformational Analysis
- A5.1.2 Energy Profile: a Global Information
- A5.1.3 Definition of Conformational Analysis
- A5.2. Potential Surface
- A5.2.1 Conformational Potential Surface: One Rotation
- A5.2.2 Conformational Potential Surface: Two Rotations
- A5.2.3 Conformational Potential Surface
- A5.2.4 Special Forms
- A5.2.5 Interconversion Between Conformers
- A5.2.6 Energy Barriers
- A5.2.7 Interconversion Pathway
- A5.3. Conformational Analysis
- A5.3.1 Conformational Analysis Principles
- A5.3.2 Systematic Scanning of All Potential Surfaces
- A5.3.3 Systematic Scanning is Time Consuming
- A5.3.4 How to Reduce Conformational Search?
- A5.3.5 One Conformer Represents a Whole Family
- A5.3.6 Working with a Set of Representative Conformers
- A5.3.7 Sildenafil Example
- A5.3.8 Family Representatives: Small Rings
- A5.3.9 Family Representatives: Acyclic Bonds
- A5.3.10 Consequence: Minimization Treatments
- A5.3.11 Example: Analysis of Elementary Fragments
- A5.3.12 Example: Generation of Representative Conformers
- A5.3.13 Example: Results of Conformational Analysis
- A5.3.14 Conformational Analysis Principles: Summary
- A5.4. Minimizations
- A5.4.1 Definition of the Minimization of a Conformer
- A5.4.2 Improved Geometries and Good Energies
- A5.4.3 The Minimization Treatment
- A5.4.4 How Does Minimization Works?
- A5.4.5 Minimization Methods
- A5.4.6 Many Variables Are Minimized
- A5.4.7 Minimization is a Time-Consuming Treatment
- A5.5. Examples of Minimization
- A5.5.1 Minimization with Stretching Strain
- A5.5.2 Minimization with Bending Strain
- A5.5.3 Minimization with Torsional Strain
- A5.5.4 Minimization with Van der Waals Strain
- A5.5.5 Minimization with Electrostatic Component
- A5.5.6 Minimization with Hydrogen Bond Component
- A5.5.7 Typical Minimization Example
- A5.5.8 Distribution of Energy Strain
- A5.6. Conformational Analysis in Drug Design
- A5.6.1 Conformational Analysis in Drug Design
- A5.6.2 Energy of the Bioactive Form
- A5.6.3 Low Energy of the Bioactive Conformation
- A5.6.4 Geometry of the Bioactive Conformation
- A5.6.5 The Experienced Molecular Modeler
- A5.6.6 Common Errors Made with Minimization
- A5.6.7 Example 1
- A5.6.8 Example 2
- A5.7. Molecular Dynamics
- A5.7.1 Molecular Dynamics
- A5.7.2 Theoretical Basis of Molecular Dynamic Calculations
- A5.7.3 Local Minima and Global Minimum
- A5.7.4 Simulated Annealing, a Special Type of Dynamics
- A5.7.5 Coherency of Molecular Motions
- A5.7.6 A Typical Molecular Dynamics Run
- A5.8. CHAPTER QUIZZES (Available only in Teaching Package)
- A5.8.1 Quiz 1
- A5.8.2 Quiz 2
- A5.8.3 Quiz 3
- A5.8.4 Quiz 4
- A5.8.5 Quiz 5
- A5.8.6 Quiz 6
- A5.8.7 Quiz 7
- A5.8.8 Quiz 8
- A5.8.9 Quiz 9
- A5.8.10 Quiz 10
- A5.8.11 Quiz 11
- A5.8.12 Quiz 12
- A5.8.13 Quiz 13
- A5.8.14 Quiz 14
- A5.8.15 Quiz 15
- A5.8.16 Quiz 16
- A5.8.17 Quiz 17
- A5.8.18 Quiz 18
- A5.8.19 Quiz 19
- A5.8.20 Quiz 20
- A5.8.21 Quiz 21
- A5.8.22 Quiz 22
- A5.8.23 Quiz 23
- A5.8.24 Quiz 24
- A5.8.25 Quiz 25
- A5.8.26 Quiz 26
- A5.8.27 Quiz 27
- A5.8.28 Quiz 28
- A5.8.29 Quiz 29
- A5.8.30 Quiz 30
- A5.8.31 Quiz 31
- A5.8.32 Quiz 32
- A5.8.33 Quiz 33
- A5.8.34 Quiz 34
- A5.8.35 Quiz 35
- A5.8.36 Quiz 36
- A5.8.37 Quiz 37
- A5.8.38 Quiz 38
- A5.8.39 Quiz 39
- A5.8.40 Quiz 40
- A5.8.41 Quiz 41
- A6. SELECTED EXAMPLES IN 3D ANALYSIS
- A6.1. Conformational Analysis
- A6.1.1 Ethane
- A6.1.2 n-Butane
- A6.1.3 1-Butene
- A6.1.4 Butadiene
- A6.1.5 Amide
- A6.1.6 Cyclohexane
- A6.2. Conjugated Systems
- A6.2.1 Butadiene
- A6.2.2 Pentenone
- A6.2.3 Dipyrrole
- A6.2.4 Biphenyl
- A6.2.5 Atropisomerism of Biphenyls
- A6.2.6 Binaphthyl
- A6.3. Aromatic Systems
- A6.3.1 Planarity of Polyaromatic Systems
- A6.3.2 Distorted Naphthalene
- A6.3.3 Annelated Polyaromatic Benzenes
- A6.4. Cyclic Systems
- A6.4.1 Why Substituents Prefer to be Equatorial?
- A6.4.2 Mono-Substituted Cyclohexanes
- A6.4.3 t-Bu
- A6.4.4 Phenyl
- A6.4.5 Methyl
- A6.4.6 Hydroxy
- A6.4.7 Example of Preferred Axial Conformer
- A6.4.8 Di-Methyl-1,2-Cyclohexane
- A6.4.9 Trans
- A6.4.10 Cis
- A6.4.11 Di-Methyl-1,3-Cyclohexane
- A6.4.12 Trans
- A6.4.13 Cis
- A6.4.14 Di-Methyl-1,4-Cyclohexane
- A6.4.15 Trans
- A6.4.16 Cis
- A6.4.17 Trans 1,3-Di-t-Butyl-Cyclohexane
- A6.4.18 Chloro-2 Cyclohexanone
- A6.5. Other Systems
- A6.5.1 Decalins
- A6.5.2 Cis-decalin
- A6.5.3 Methyl-Cis-decalin
- A6.5.4 Trans-decalin
- A6.5.5 Interactions of Aromatic Rings
- A6.5.6 Geometry of Ester Groups
- A6.5.7 Cyclic Ester
- A6.5.8 Geometry of Amide Groups
- A6.5.9 Substituted Amide
- A6.5.10 Cyclic Amide
- A7. MOLECULAR GRAPHICS
- A7.1. Introduction
- A7.1.1 Importance of Molecular Graphics
- A7.1.2 Almost Science Fiction
- A7.1.3 History of Molecular Visualizations
- A7.1.4 Commercially Available Molecular Kits
- A7.1.5 Progress in Graphical Hardware and Algorithms
- A7.1.6 Algorithm 1
- A7.1.7 Algorithm 2
- A7.1.8 Molecular Graphics Functions
- A7.2. 3D Perception
- A7.2.1 The Perception of the Third Dimension
- A7.2.2 From 3D Coordinates to Screen Coordinates
- A7.2.3 Real Time Manipulation
- A7.2.4 Depth Cueing
- A7.2.5 Perspective
- A7.2.6 Stereo
- A7.2.7 Hardware Stereo
- A7.3. Visualization
- A7.3.1 3D Representation of Small Molecules
- A7.3.2 Line
- A7.3.3 Stick
- A7.3.4 Ball & Stick
- A7.3.5 CPK
- A7.3.6 Quality of Rendering
- A7.3.7 Atomic Color-Code Convention
- A7.3.8 Coloring Molecules or Sets of Atoms
- A7.3.9 By Atom-type
- A7.3.10 By Molecule
- A7.3.11 By Color
- A7.3.12 By Properties
- A7.3.13 Labeling Functionalities
- A7.3.14 Atom Labels
- A7.3.15 Atom Numbering
- A7.3.16 Proteins Representation
- A7.3.17 Carbon Alpha
- A7.3.18 Ribbon Representation
- A7.3.19 Ribbon Types
- A7.3.20 Visualization of Protein Properties
- A7.4. Editing & Manipulation
- A7.4.1 Structure Manipulation & Editing
- A7.4.2 Add Atoms Function
- A7.4.3 Delete Atoms Function
- A7.4.4 Fuse Atoms Function
- A7.4.5 Connect atoms Function
- A7.4.6 3D Molecular Constructions
- A7.4.7 Real-Time Rotations, Translations and Zoom
- A7.4.8 Translations
- A7.4.9 Rotations
- A7.4.10 Zoom
- A7.4.11 Control of Torsion Angles
- A7.4.12 Slab and Clip
- A7.5. Surfaces & Volumes
- A7.5.1 Concept and Definition of Molecular Surfaces
- A7.5.2 Van der Waals
- A7.5.3 Solvent
- A7.5.4 Connolly
- A7.5.5 Surface Types
- A7.5.6 Normal
- A7.5.7 Transparent
- A7.5.8 Dots
- A7.5.9 Visualization of Properties on Molecular Surfaces
- A7.5.10 Color Coded
- A7.5.11 Visualization of Properties on Molecular Surfaces
- A7.5.12 The Visualization of Volumes
- A7.5.13 Mathematical Boolean Operations with Volumes
- A7.6. Visualizing Interactions
- A7.6.1 Visualization of Hydrogen Bonds
- A7.6.2 Visualization of Molecular Bumps
- A7.6.3 Surface Representations for Bump Analyses
- A7.6.4 Complementary Surface Properties
- A7.6.5 Electrostatic Potentials
- A7.6.6 Lipophilicity Potentials
- A7.6.7 Visualization of Intramolecular Interaction
- A7.6.8 Schematic Complex Interaction
- A7.6.9 Visualization of a Complex Cavity
- A7.6.10 Results of Quantum Mechanical Calculations
- A7.7. CHAPTER QUIZZES (Available only in Teaching Package)
- A7.7.1 Quiz 1
- A7.7.2 Quiz 2
- A7.7.3 Quiz 3
- A7.7.4 Quiz 4
- A7.7.5 Quiz 5
- A7.7.6 Quiz 6
- A7.7.7 Quiz 7
- A7.7.8 Quiz 8
- A7.7.9 Quiz 9
- A7.7.10 Quiz 10
- A7.7.11 Quiz 11
- A7.7.12 Quiz 12
- A7.7.13 Quiz 13
- A7.7.14 Quiz 14
- A7.7.15 Quiz 15
- A7.7.16 Quiz 16
- A7.7.17 Quiz 17
- A7.7.18 Quiz 18
- A7.7.19 Quiz 19
- A7.7.20 Quiz 20
- A7.7.21 Quiz 21
- A7.7.22 Quiz 22
- A7.7.23 Quiz 23
- A7.7.24 Quiz 24
- A7.7.25 Quiz 25
- A7.7.26 Quiz 26
- A7.7.27 Quiz 27
- A7.7.28 Quiz 28
- A7.7.29 Quiz 29
- B. PROTEIN STRUCTURE AND MODELING
- B1. STRUCTURAL BIOINFORMATICS
- B1.1. Introduction to Structural Bioinformatics
- B1.1.1 Challenges in the Post Genomic Era
- B1.1.2 The Informational Chaos
- B1.1.3 Integration through Computational Science
- B1.1.4 Structural Bioinformatics
- B1.1.5 Grouping Fields into One Discipline
- B1.1.6 3D Basis of Structural Bioinformatics
- B1.1.7 The Structural Genomics Effort
- B1.1.8 The Protein Structure Initiative
- B1.1.9 Strategy of the Protein Structure Initiative
- B1.1.10 The Structural Genomics Consortium
- B1.1.11 Global Planning of Structural Genomics
- B1.1.12 The Impact of Structural Genomics
- B1.1.13 The Relationship between Structure and Function
- B1.1.14 Example of a Structure-Function Relationship
- B1.1.15 Learning from Evolution
- B1.1.16 Learning from Structural Folds
- B1.1.17 Learning from Molecular Shape
- B1.1.18 Example of Knowledge Derived from 3D Structure
- B1.1.19 Is Structure Sufficient to Predict Function?
- B1.1.20 Exploiting Knowledge to Design New Drugs
- B1.1.21 Bridge between Genomics and Drug Discovery
- B1.1.22 Tools Developed by Structural Bioinformatics
- B1.2. Architecture of Biomolecules
- B1.2.1 Biomolecules in the Cell
- B1.2.2 DNA/RNA Structure
- B1.2.3 DNA is the Genetic Material
- B1.2.4 DNA Variability
- B1.2.5 Importance of the DNA 3D Structure
- B1.2.6 The Building Blocks
- B1.2.7 Base
- B1.2.8 Sugar
- B1.2.9 Phosphate
- B1.2.10 Putting the Building Blocks Together
- B1.2.11 Nomenclature of Nucleotides and Nucleosides
- B1.2.12 Nucleotides of Nucleic Acids
- B1.2.13 The Double Helix Structure
- B1.2.14 DNA Helices are Antiparallel
- B1.2.15 Hydrogen Bonding Pattern
- B1.2.16 Aromatic Base Stacking
- B1.2.17 Major and Minor Grooves
- B1.2.18 DNA forms
- B1.2.19 G-Quadruplex Conformation
- B1.2.20 DNA versus RNA
- B1.2.21 3D Folds of RNA
- B1.2.22 Protein Structure
- B1.2.23 Proteins are Fundamental to Life
- B1.2.24 Structural Diversity of Proteins
- B1.2.25 Importance of Protein 3D Structures
- B1.2.26 Chemical Nature of Proteins
- B1.2.27 Challenges in Understanding Protein Structure
- B1.2.28 Protein Structure Complexity
- B1.2.29 The Four Levels of Protein Architecture
- B1.2.30 Primary Structure
- B1.2.31 Secondary Structure
- B1.2.32 Tertiary Structure
- B1.2.33 Quaternary Structure
- B1.3. Biomolecular Properties
- B1.3.1 Protein Flexibility and Motion
- B1.3.2 Importance of Dynamic Motions in Biological Processes
- B1.3.3 Example of Function: ATP Synthase
- B1.3.4 Example of Function: DNA Biosynthesis
- B1.3.5 Example of Function: Molecular Switch
- B1.3.6 Example of Induced-Fit: RNA-Protein Recognition
- B1.3.7 Example of Induced-Fit: Ubiquitous Proteins
- B1.3.8 Types of Molecular Motions
- B1.3.9 Time Scale of Protein Motion
- B1.3.10 Methods to Study Protein Motions
- B1.3.11 Experimental Techniques to Study Protein Motions
- B1.3.12 Simulation Methods to Study Protein Motions
- B1.3.13 Normal Mode Analyses (NMA)
- B1.3.14 Molecular Dynamics vs Normal Mode Analyses
- B1.3.15 Database of Macromolecular Movements
- B1.4. Assembly of Biomolecules
- B1.4.1 Biological Molecule Association
- B1.4.2 Molecular Recognition
- B1.4.3 The Recognition Process
- B1.4.4 Complementary Features Upon Binding
- B1.4.5 Role of Native Protein Configuration
- B1.4.6 Tolerance Upon Binding
- B1.4.7 The "Induced-Fit" Theory
- B1.4.8 Example of Enzyme Adaptation to Inhibitor Binding
- B1.4.9 Example of Ligand Adaptation upon Binding
- B1.4.10 Maximizing Surface Contacts
- B1.4.11 Motions Associated to Induced-Fit
- B1.4.12 Experimental Evidence of the Induced-Fit Model
- B1.4.13 Large Rearrangements
- B1.4.14 Role of Large Rearrangements
- B1.4.15 The Domino Effect
- B1.4.16 Proteins Described as Ensemble of Conformations
- B1.4.17 Energy Landscape of a Protein
- B1.4.18 Conformational Selection Operated by a Ligand
- B1.4.19 Energetic Induction Upon Binding
- B1.4.20 Forces Involved in Molecular Recognition
- B1.4.21 Van der Waals Forces
- B1.4.22 Electrostatic Interactions
- B1.4.23 Hydrogen Bonds
- B1.4.24 Solvent Effect
- B1.4.25 The Role of the Solvent
- B1.4.26 The Hydrophobic Effect
- B1.4.27 The Entropic Effects
- B1.4.28 Enthalpy-Entropy Compensation
- B1.4.29 Assessing Binding Interactions
- B1.4.30 Free Energy of Binding
- B1.4.31 Importance of Free Energy of Binding
- B1.4.32 Experimental Measures of Binding Affinities
- B1.4.33 Titration Curve to Measure Kd
- B1.4.34 Scatchard-Rosenthal Plots
- B1.4.35 Conversion of Kd into Energies
- B1.4.36 Theoretical Prediction of Binding Energies
- B1.4.37 Solving the Schrodinger Equation
- B1.4.38 Molecular Mechanics
- B1.4.39 Force-Field
- B1.4.40 Example of Force-Fields
- B1.4.41 Other Methods
- B1.4.42 Incorporation of the Solvent
- B1.5. Obtaining Macromolecular 3D-Structures
- B1.5.1 Experimental Methods
- B1.5.2 X-ray Crystallography
- B1.5.3 Protein Production and Purification
- B1.5.4 Growing of Single Crystal
- B1.5.5 The Single Crystal
- B1.5.6 Collecting the Diffraction Data
- B1.5.7 Recovering the Phase Angle
- B1.5.8 Structure Determination and Refinement
- B1.5.9 Atomic Coordinates
- B1.5.10 The Advantages of X-ray Crystallography
- B1.5.11 The Limitations of X-ray Crystallography
- B1.5.12 NMR Spectroscopy
- B1.5.13 NMR Concepts
- B1.5.14 Spin-Spin Coupling
- B1.5.15 Data Collection
- B1.5.16 Structure Determination
- B1.5.17 Analysis
- B1.5.18 The Advantages of NMR
- B1.5.19 The Limitations of NMR
- B1.5.20 Electron Microscopy
- B1.5.21 Basic Concept
- B1.5.22 The Advantages of Electron Microscopy
- B1.5.23 The Limitations of Electron Microscopy
- B2. PROTEIN STRUCTURE
- B2.1. Structural and Functional Diversity of Proteins
- B2.1.1 Proteins are Fundamental to Life
- B2.1.2 Great Diversity of Protein Biological Functions
- B2.1.3 Chemical Nature of Proteins
- B2.1.4 Structural Diversity of Proteins
- B2.2. Link between Protein Sequence, Folding and Function
- B2.2.1 Importance of Protein 3D Structures
- B2.2.2 Protein Folding
- B2.2.3 Anfinsen's Dogma
- B2.2.4 Anfinsen's Dogma and Levinthal's Paradox
- B2.2.5 The Pathway Theory and Energy Funnels
- B2.2.6 Mechanisms of Protein Folding
- B2.2.7 The Protein Misfolding Problem
- B2.2.8 Challenge in Understanding Protein Structure
- B2.3. Amino Acids: Building Blocks of Proteins
- B2.3.1 Amino acids: Building Blocks of Proteins
- B2.3.2 α-Amino Acids
- B2.3.3 α-Amino Acid Stereoisomers
- B2.3.4 Diversity of the Properties of Amino Acids
- B2.3.5 Amino Acids Properties
- B2.3.6 Classification of Amino Acids Properties
- B2.3.7 Non-Standard Amino Acids
- B2.4. From Amino Acids to Proteins
- B2.4.1 Amino Acids are Linked by Peptide Bonds
- B2.4.2 Peptide Biosynthesis
- B2.4.3 Polymer Amino-Acids
- B2.4.4 Length of Proteins
- B2.4.5 More than One Polypeptide Chain
- B2.4.6 Conjugated Proteins
- B2.4.7 Examples of Conjugated Proteins
- B2.4.8 Cross-Linked Polypeptide Chains
- B2.5. Geometry of Proteins and Peptides
- B2.5.1 Peptide Bonds are Planar
- B2.5.2 Why the Peptide Bond is Planar?
- B2.5.3 Cis and Trans Isomers of the Peptide Bond
- B2.5.4 Trans Isomer Favored
- B2.5.5 Isomers of Proline
- B2.5.6 Peptide Torsion Angles
- B2.5.7 Conformational Freedom
- B2.5.8 Conformational Complexity of Polypeptide Chains
- B2.5.9 Not All φ/ψ Torsion Angles are Possible
- B2.5.10 The Ramachandran Plot
- B2.5.11 φ and ψ Distribution
- B2.5.12 Interactive Ramachandran Plot
- B2.5.13 Torsion Angles Observed in Proteins
- B2.5.14 Glycine Residue Torsion Angles
- B2.5.15 Side Chain Conformations
- B2.5.16 Side Chain Atomic and 3D Nomenclature
- B2.5.17 Side Chain Conformations
- B2.5.18 Non-Rotameric Side Chain Conformations
- B2.6. Protein Structure Overview
- B2.6.1 Protein Structure Complexity
- B2.6.2 The Four Levels of Protein Architecture
- B2.6.3 Primary Structure
- B2.6.4 Secondary Structure
- B2.6.5 Tertiary Structure
- B2.6.6 Quaternary Structure
- B2.6.7 Forces Involved in Protein Stability
- B2.6.8 Proteins are not Static
- B2.6.9 Representing Protein Structures
- B2.6.10 Wireframe Representation
- B2.6.11 Ball and Stick Representation
- B2.6.12 Cα Trace Representation
- B2.6.13 Ribbon Representation
- B2.6.14 Cartoon Representation
- B2.6.15 Space Filling - CPK Representation
- B2.6.16 Surface Representation
- B2.7. Primary Structure
- B2.7.1 Primary Structure
- B2.7.2 Unique Primary Structure for Each Protein
- B2.7.3 Primary Sequence and Protein Properties
- B2.8. Secondary Structure
- B2.8.1 Secondary Structure
- B2.8.2 Periodic and Non Periodic Secondary Structure Elements
- B2.8.3 Hydrogen Bonds in Secondary Structure Elements
- B2.8.4 The α-Helix
- B2.8.5 Packing of the α-Helix
- B2.8.6 φ and ψ Torsion Angles of the α-Helix
- B2.8.7 Two Enantiomeric α-Helices
- B2.8.8 Geometry Described with Pitch and Rise
- B2.8.9 Helix Macro-Dipole
- B2.8.10 Amphipathic Character of the α Helix
- B2.8.11 3(10)-Helix and π-Helix
- B2.8.12 Helices Geometrical Parameters
- B2.8.13 Occurrence of Helices in Proteins
- B2.8.14 The β-Sheet
- B2.8.15 The β-Strand Unit
- B2.8.16 φ and ψ Torsion Angles in β-Sheets
- B2.8.17 Stability of the β-Sheet
- B2.8.18 Parallel and Anti-Parallel β-Sheets
- B2.8.19 Occurrence of β-Sheets in Proteins
- B2.8.20 Twist of the β-sheet
- B2.8.21 Turns
- B2.8.22 β-Turns
- B2.8.23 φ and ψ Torsion Angles of β Turns
- B2.8.24 Non-Regular Coil and Loops
- B2.8.25 Coil
- B2.8.26 Loops
- B2.9. Super-Secondary Structure (Motifs)
- B2.9.1 Super-Secondary Structures and Motifs
- B2.9.2 Classification of Super-Secondary Structures
- B2.9.3 All β super-secondary structures
- B2.9.4 β-Hairpin
- B2.9.5 β-Meander
- B2.9.6 Greek-Key
- B2.9.7 All α Super-Secondary Structures
- B2.9.8 αα-Hairpin
- B2.9.9 αα-Corners
- B2.9.10 EF Hand
- B2.9.11 Helix-Turn-Helix
- B2.9.12 Four-Helix Bundle
- B2.9.13 Mixed α & β Super-Secondary Structures
- B2.9.14 β-α-β Motif
- B2.9.15 Rossmann Fold
- B2.10. Tertiary Structure
- B2.10.1 Tertiary Structure
- B2.10.2 Domains in the Tertiary Structure
- B2.10.3 Domains and Sequence
- B2.10.4 Domains and Function
- B2.10.5 New Look on Proteins Levels of Architecture
- B2.10.6 Blurred Boundaries
- B2.10.7 Tertiary Structure Patterns: Folds
- B2.10.8 Fold Diversity
- B2.10.9 Protein Folds and Function
- B2.10.10 Classification of Protein Folds
- B2.10.11 Mainly α Folds
- B2.10.12 Mainly β Folds
- B2.10.13 Mixed α-β Folds
- B2.10.14 Databases of Folds
- B2.11. Quaternary Structure
- B2.11.1 Quaternary Structure
- B2.11.2 Dimers, Trimers, Tetramers etc...
- B2.11.3 Homo-Oligomers: Identical Polypeptide Chains
- B2.11.4 Hetero-Oligomers: Different Polypeptide Chains
- B2.12. Structural Classification of Proteins
- B2.12.1 Structural Classification of Proteins
- B2.12.2 Globular Proteins
- B2.12.3 Hydrophilic Surface and Hydrophobic Core
- B2.12.4 Hydrophobic Effect
- B2.12.5 Hydration Layer
- B2.12.6 Membrane Proteins
- B2.12.7 The Lipid Bilayer
- B2.12.8 Membrane Model
- B2.12.9 Membrane Proteins Types
- B2.12.10 Transmembrane Protein Surface
- B2.12.11 Transmembrane Protein Folds
- B2.12.12 Fibrous Proteins
- B2.12.13 Collagen
- B2.12.14 α-Keratin
- B2.12.15 Silk Fibroin
- B2.13. Perspectives
- B2.13.1 The History
- B2.13.2 The Pharmaceutical Connection
- B2.13.3 A Fascinating Field
- B2.14. CHAPTER QUIZZES (Available only in Teaching Package)
- B2.14.1 Quiz 1
- B2.14.2 Quiz 2
- B2.14.3 Quiz 3
- B2.14.4 Quiz 4
- B2.14.5 Quiz 5
- B2.14.6 Quiz 6
- B2.14.7 Quiz 7
- B2.14.8 Quiz 8
- B2.14.9 Quiz 9
- B2.14.10 Quiz 10
- B2.14.11 Quiz 11
- B2.14.12 Quiz 12
- B2.14.13 Quiz 13
- B2.14.14 Quiz 14
- B2.14.15 Quiz 15
- B2.14.16 Quiz 16
- B2.14.17 Quiz 17
- B2.14.18 Quiz 18
- B2.14.19 Quiz 19
- B2.14.20 Quiz 20
- B2.14.21 Quiz 21
- B2.14.22 Quiz 22
- B2.14.23 Quiz 23
- B2.14.24 Quiz 24
- B2.14.25 Quiz 25
- B2.14.26 Quiz 26
- B2.14.27 Quiz 27
- B2.14.28 Quiz 28
- B2.14.29 Quiz 29
- B2.14.30 Quiz 30
- B2.14.31 Quiz 31
- B2.14.32 Quiz 32
- B2.14.33 Quiz 33
- B2.14.34 Quiz 34
- B2.14.35 Quiz 35
- B2.14.36 Quiz 36
- B2.14.37 Quiz 37
- B2.14.38 Quiz 38
- B2.14.39 Quiz 39
- B2.14.40 Quiz 40
- B2.14.41 Quiz 41
- B2.14.42 Quiz 42
- B2.14.43 Quiz 43
- B2.14.44 Quiz 44
- B2.14.45 Quiz 45
- B2.14.46 Quiz 46
- B2.14.47 Quiz 47
- B2.14.48 Quiz 48
- B2.14.49 Quiz 49
- B2.14.50 Quiz 50
- B2.14.51 Quiz 51
- B2.14.52 Quiz 52
- B2.14.53 Quiz 53
- B2.14.54 Quiz 54
- B2.14.55 Quiz 55
- B2.14.56 Quiz 56
- B2.14.57 Quiz 57
- B2.14.58 Quiz 58
- B2.14.59 Quiz 59
- B2.14.60 Quiz 60
- B2.14.61 Quiz 61
- B2.14.62 Quiz 62
- B2.14.63 Quiz 63
- B2.14.64 Quiz 64
- B2.14.65 Quiz 65
- B2.14.66 Quiz 66
- B2.14.67 Quiz 67
- B2.14.68 Quiz 68
- B2.14.69 Quiz 69
- B2.14.70 Quiz 70
- B2.14.71 Quiz 71
- B2.14.72 Quiz 72
- B2.14.73 Quiz 73
- B2.14.74 Quiz 74
- B2.14.75 Quiz 75
- B2.14.76 Quiz 76
- B2.14.77 Quiz 77
- B2.14.78 Quiz 78
- B2.14.79 Quiz 79
- B2.14.80 Quiz 80
- B2.14.81 Quiz 81
- B2.14.82 Quiz 82
- B2.14.83 Quiz 83
- B2.14.84 Quiz 84
- B2.14.85 Quiz 85
- B2.14.86 Quiz 86
- B2.14.87 Quiz 87
- B2.14.88 Quiz 88
- B2.14.89 Quiz 89
- B4. MOLECULAR DOCKING
- B4.1. Introduction to Computational Docking
- B4.1.1 Molecular Recognition
- B4.1.2 Molecular Recognition Process: Molecular Docking
- B4.1.3 Understanding Molecular Recognition
- B4.1.4 Molecular Docking Models
- B4.1.5 The Lock and Key Theory
- B4.1.6 The Induced-Fit Theory
- B4.1.7 The Conformation Ensemble Model
- B4.1.8 From the Lock and Key to the Ensemble Model
- B4.1.9 Experimental Methods to Study Molecular Docking
- B4.1.10 Limitations of Experimental Techniques
- B4.1.11 A Bottleneck in Drug Discovery
- B4.1.12 Triggering the Computational Docking Discipline
- B4.1.13 Definition of Computational Docking
- B4.1.14 Applications of Computational Docking
- B4.2. The Docking Problem
- B4.2.1 The Docking Problem
- B4.2.2 Great Diversity of Molecular Interactions
- B4.2.3 Atomic Basis of Molecular Recognition
- B4.2.4 Definition of the "Pose"
- B4.2.5 Docking Viewed as a Black Box
- B4.2.6 Current Computational Docking Programs
- B4.2.7 Simulation and non-Simulation Approaches
- B4.2.8 Simulation Approaches
- B4.2.9 Non-Simulation Approaches
- B4.2.10 Molecular Complementarity in Computational Docking
- B4.2.11 Shape Complementarity
- B4.2.12 Chemical Complementarity
- B4.2.13 Energy Dictates Molecular Associations
- B4.2.14 Find a Complex that Minimizes the Energy
- B4.2.15 Accounting for Molecular Flexibility in Docking
- B4.2.16 Flexible Docking: Increasing Levels of Complexity
- B4.2.17 Initial Data and Nature of the Docking Difficulty
- B4.2.18 Bound Docking
- B4.2.19 Unbound Docking
- B4.2.20 Modeled Docking
- B4.2.21 The Three Generations in Computational Docking
- B4.2.22 Three Components of Docking Software
- B4.3. System Representation
- B4.3.1 Molecular Representation
- B4.3.2 Atomic Representation
- B4.3.3 Complexity of the Atomic Repesentation
- B4.3.4 Internal Coordinates
- B4.3.5 Protein Preparation
- B4.3.6 Small Molecule Preparation
- B4.3.7 Surface Representation
- B4.3.8 Molecular Surface Matching
- B4.3.9 Surface-Based Representation
- B4.3.10 Accessible Surface Area
- B4.3.11 Solvent Contact & Reentrant Surfaces
- B4.3.12 Example of Contact & Reentrant Surface
- B4.3.13 Describing the Molecular Shape
- B4.3.14 Connolly's Contact and Reentrant Surfaces
- B4.3.15 Sparse Surface
- B4.3.16 Delaunay Triangulation
- B4.3.17 "Knob" and "Hole" Descriptors
- B4.3.18 Using Knobs and Holes for Complementarity
- B4.3.19 Other Examples of Shape Descriptors
- B4.3.20 Grid Representation
- B4.3.21 Use of GRID Potentials to Simplify the Docking
- B4.3.22 Assessing Shape Complementarity Using Grid
- B4.4. Scoring Methods
- B4.4.1 Need to Assess the Quality of Docked Complexes
- B4.4.2 A Good Understanding of the Binding
- B4.4.3 Important Questions
- B4.4.4 Molecular Determinants for Binding
- B4.4.5 Interaction Forces and Binding Energies
- B4.4.6 Favorable Forces
- B4.4.7 Unfavorable Forces
- B4.4.8 Desolvation Energies
- B4.4.9 Entropic Effects
- B4.4.10 Calculation of the Binding Energies
- B4.4.11 Free Energy Equations
- B4.4.12 Conversion of K to Energies
- B4.4.13 Difficulty of Calculating Free Energies of Binding ΔG
- B4.4.14 Approximating ΔG by Molecular Mechanics
- B4.4.15 Force-Field Calculations
- B4.4.16 CHARMM Force Field to Score the Docking
- B4.4.17 Approximating ΔG by Quantum Mechanics
- B4.4.18 Development of Scoring Functions for Docking
- B4.4.19 Scoring Functions
- B4.4.20 Empirical Scoring Functions
- B4.4.21 Example of Empirical Scoring Function
- B4.4.22 Knowledge-Based Scoring Functions
- B4.4.23 The Statistical Analyses
- B4.4.24 Knowledge-Based Potentials
- B4.4.25 The DrugScore Program
- B4.4.26 DrugScore: The Thrombin Example
- B4.4.27 Refinement of Scoring Functions
- B4.4.28 Other Scoring Methods
- B4.4.29 Shape and Property Complementarity Scoring
- B4.4.30 Method to Measure Shape Complementarity
- B4.4.31 Free Energy Perturbation
- B4.5. Rigid Docking Methods
- B4.5.1 Docking Algorithms
- B4.5.2 The Mathematical Problem
- B4.5.3 Two Docking Philosophies
- B4.5.4 The Feature-Based Matching Approach
- B4.5.5 Docking Using Feature-Based Methods
- B4.5.6 Match Complementarity or Similarity Features
- B4.5.7 Components of Feature-Based Matching Methods
- B4.5.8 Step 1: Feature Extraction
- B4.5.9 Step 2: Feature Matching
- B4.5.10 Step 3: Transformation (Assembly)
- B4.5.11 Step 4: Filtering and Scoring
- B4.5.12 Virtual Screening and De Novo Design
- B4.5.13 Programs with Feature-Based Matching Methods
- B4.5.14 Algorithms of Matching
- B4.5.15 Clique-Search Based Approaches
- B4.5.16 Goal of the Docking Algorithm
- B4.5.17 Distance Compatibility Graph
- B4.5.18 Clique Detection Methods
- B4.5.19 Pose-Clustering
- B4.5.20 Searching for Compatible Triangles
- B4.5.21 Transformation that Align a Maximum of Triangles
- B4.5.22 Complementarity and Similarity Matching
- B4.5.23 Speed up of Pose-Clustering
- B4.5.24 The Bottleneck of Pose-Clustering
- B4.5.25 Geometric Hashing
- B4.5.26 Fast Retrieval of Matching Features
- B4.5.27 Invariant Representation of Features
- B4.5.28 Improvement of Pose-Clustering
- B4.5.29 PatchDock Example
- B4.5.30 The Stepwise Search Approach
- B4.5.31 Components of a Stepwise Docking Program
- B4.5.32 Exhaustive and Stochastic Search
- B4.5.33 Exhaustive vs. Stochastic Search
- B4.5.34 Exhaustive Search
- B4.5.35 Mapped-Grid Method
- B4.5.36 Physico-Chemical Properties of the Receptor
- B4.5.37 Assessing Shape Complementarity
- B4.5.38 Fast-Fourier Transform (FFT) Method
- B4.5.39 FFT vs. Exhaustive Method
- B4.5.40 FFT - Geometric Shape Complementarity
- B4.5.41 FFT - Different Scores
- B4.5.42 Docking of Plastocyanin and Cytochrome C
- B4.5.43 Spherical Polar Fourier Correlations - Fast FFT
- B4.5.44 Stochastic Algorithms
- B4.5.45 A Typical Computational Docking Program
- B4.5.46 Optimization Methods to Find the Best Solution
- B4.5.47 Monte Carlo Methods
- B4.5.48 Simulated Annealing
- B4.5.49 Genetic Algorithms (GA)
- B4.5.50 General Principle of GA
- B4.5.51 Creating a New Generation
- B4.5.52 Simulating the Reproduction Process
- B4.5.53 Steps in Genetic Algorithms
- B4.5.54 Lamarckian Genetic Algorithm
- B4.5.55 Tabu Search
- B4.5.56 Tabu Algorithm
- B4.5.57 Avoiding Being Trapped in a Local Minimum
- B4.5.58 Better Exploration of the Space
- B4.5.59 The Hybrid Docking Method
- B4.6. Methods for Incorporating Flexibility
- B4.6.1 Implementation of Flexibility into Docking Software
- B4.6.2 Degrees of Freedom in Flexible Docking
- B4.6.3 Possible Classification of Methods for Flexibility
- B4.6.4 Classification of Methods
- B4.6.5 Incorporating Small Molecule Flexibility
- B4.6.6 Modeling Small Molecules as Flexible Entities
- B4.6.7 Small Molecule Flexibility
- B4.6.8 Integration of Ligand Flexibility and Protein Structure
- B4.6.9 Methods for Handling Ligand Flexibility Explicitly
- B4.6.10 The Ensemble Docking Method
- B4.6.11 Advantage of the Ensemble Docking Method
- B4.6.12 The FLOG Software
- B4.6.13 Problem of the Ensemble Docking Approach
- B4.6.14 The Improved Ensemble Docking Method
- B4.6.15 Remove Redundancy in the Rigid Fragment
- B4.6.16 Remove Redundancy in the Flexible Fragment
- B4.6.17 Score: Sum of Atom Interactions
- B4.6.18 Step-1: Conformational Analysis
- B4.6.19 Step-2: Superimposition and Positioning
- B4.6.20 Step-3: Conformational Analysis
- B4.6.21 Dramatic Improvement in Computing Time
- B4.6.22 Efficient Treatment of Clashes
- B4.6.23 Validation of the Lorber-Shoichet Method
- B4.6.24 Extension to Analog Compounds
- B4.6.25 The Fragmentation Docking Method
- B4.6.26 Place-and-Join Algorithm
- B4.6.27 Principle of the Place-and-Join Method
- B4.6.28 Difficulty of the Place and Join Method
- B4.6.29 Incremental-Based Methods
- B4.6.30 Incremental Algorithm
- B4.6.31 Stochastic Search Methods
- B4.6.32 GOLD
- B4.6.33 Incorporating Protein Flexibility
- B4.6.34 Importance of Modeling Protein Flexibility
- B4.6.35 Historical Note
- B4.6.36 Flexibility Through Soft Scoring Functions
- B4.6.37 Reduce the Importance of Steric Clashes
- B4.6.38 Soft Van der Waals Repulsion Functions
- B4.6.39 Decreasing Van der Waals Radii
- B4.6.40 Soft Electrostatic Repulsion Potentials
- B4.6.41 Soft Scoring Functions in Protein-Protein Docking
- B4.6.42 Implicit Flexibility in Protein-Protein Docking
- B4.6.43 Problems with Soft Scoring
- B4.6.44 Soft Scoring as a First Filtering Method
- B4.6.45 Protein Side-Chains Flexibility
- B4.6.46 Importance of Modeling Side-Chain Mobility
- B4.6.47 Determine the Optimum Combination of Side-Chains
- B4.6.48 Combinatorial Explosion
- B4.6.49 Side Chain Rotamer Libraries
- B4.6.50 From Folding to Docking
- B4.6.51 The Leach Algorithm
- B4.6.52 Generation and Minimization of Complexes
- B4.6.53 Other Optimization Methods
- B4.6.54 Restricting Searches and Minimizations
- B4.6.55 Identify Key Residues for the Interaction
- B4.6.56 Restrict the Search to Exposed Side Chains
- B4.6.57 Backbone and Side Chain Flexibility
- B4.6.58 Conventional Methods not Adapted
- B4.6.59 The Multiple Protein Structure (MPS) Approach
- B4.6.60 Principle of the MPS Approach
- B4.6.61 Sources of Multiple Protein Structures
- B4.6.62 MPS: a Good Model for the Recognition Process
- B4.6.63 How the MPS are Exploited?
- B4.6.64 Successive and Independent Docking Treatments
- B4.6.65 Acetylcholinesterase Example
- B4.6.66 The United Protein Approach
- B4.6.67 Key Concept of FlexE
- B4.6.68 Remove Redundant Information
- B4.6.69 FlexE: Incompatibility Graph
- B4.6.70 FlexE: Search & Scoring
- B4.6.71 The Average Grid Approach
- B4.6.72 Single Grid Combining MPS Information
- B4.6.73 Scoring Tolerance with MPS-based Grids
- B4.6.74 Average Grid Approach vs. Soft Scoring
- B4.6.75 Dynamic Pharmacophore-Based Approach
- B4.6.76 Dynamic Pharmacophore Model for HIV-1 Integrase
- B4.6.77 Domain Movements
- B4.6.78 Example of Calmodulin Domain Movements
- B4.6.79 Conventional Modeling Methods are not Suited
- B4.6.80 Intrinsic Flexibility
- B4.6.81 Hinge-Bent Movements
- B4.6.82 Automated Methods for Hinge Detection
- B4.6.83 Incorporating Hinge-Bent Movements in Docking
- B4.6.84 Docking with Hinge-Bent Movements
- B4.6.85 Ball-and-Socket Motions
- B4.7. Uses of Docking in Research
- B4.7.1 Computational Docking in Drug Discovery
- B4.7.2 Virtual Screening
- B4.7.3 Increasing HTS Hit Rates
- B4.7.4 Confirm Choice of Prototype Structure
- B4.7.5 Manual Design of a New Scaffold
- B4.7.6 New Cores from a Database of Scaffolds
- B4.7.7 De Novo Design of Spacers
- B4.7.8 Modulating Protein-Protein Interactions
- B4.7.9 Query for 3D Database Searching
- B4.7.10 Creative Molecular Design Conditions
- B4.7.11 Design of Combinatorial Libraries
- B4.7.12 Understanding SAR
- B4.7.13 Reducing Multiple Hypotheses to a Single One
- B4.7.14 Series Optimization
- B4.7.15 Explaining Incomprehensible Observations
- B4.7.16 Identifying Incorrect Working Hypotheses
- B4.7.17 Align Chemically Unrelated Molecules in 3D
- B4.7.18 Improving the Solubility of a Ligand
- B4.7.19 Understand the Intrinsic Limitations of a Scaffold
- B4.7.20 Assessing the Potential of a Hit
- B4.7.21 Elucidating Exact Mode of Action
- B4.7.22 Assessing Multiple Alignment Hypotheses
- B4.7.23 Molecular Mimicry
- B4.7.24 Computational Validation of Hypotheses
- B4.8. Docking Softwares
- B4.8.1 Docking Programs
- B4.8.2 Dock
- B4.8.3 Autodock
- B4.8.4 DockVision
- B4.8.5 DockIt
- B4.8.6 FlexX
- B4.8.7 Ligin
- B4.8.8 FT-Dock
- B4.8.9 GOLD
- B4.8.10 GRAMM
- B4.8.11 Hex
- B4.8.12 eHiTS
- B4.8.13 LigandFit
- B4.8.14 FRED
- B4.8.15 Glide
- B4.8.16 Which Software is Better?
- B4.9. Future and Perspectives
- B4.9.1 Limitations in Computational Docking
- B4.9.2 Trade Off Between Efficiency and Accuracy
- B4.9.3 Screening Large Chemical Libraries
- B4.9.4 A Two Step Strategy
- B4.9.5 High-throughput Docking Using Grid-Computing
- B4.9.6 How Does it Work?
- B4.9.7 Wide In Silico Docking On Malaria (WISDOM)
- B4.9.8 Enrichment Factor
- B4.9.9 Current Status of the Docking Problem
- B4.9.10 The Docking Bottlenecks
- B4.9.11 More Effective Scoring Functions
- B4.9.12 Modeling the Solvent
- B4.9.13 Validation of Scoring Functions
- B4.9.14 Target Trainable Scoring Functions
- B4.9.15 Database of Decoys
- B4.9.16 Consensus Scoring
- B4.9.17 The Molecular Flexibility Challenge
- B4.9.18 Developing Better Models of Flexibility
- B4.9.19 Importance of Visual Docking
- B4.9.20 Requirement for Manual Docking
- B4.9.21 Illustration of Manual Docking
- B4.9.22 Manual Docking with Solid Models
- B4.9.23 Virtual Reality Docking System
- B4.9.24 Example of Docking using CAVE
- B4.9.25 Synergy Between Interactive & Automated Docking
- B4.9.26 Interactive Computer-Guided Docking
- B4.9.27 Protein-Protein Docking Benchmarks
- B4.9.28 The CAPRI Competition
- B4.9.29 Six Weeks for Submitting Predicted Complexes
- B4.9.30 Assessment of the Predictions
- B4.9.31 A New CAPRI Scoring Category
- B4.9.32 CAPRI History and Experience
- B4.9.33 Perspectives
- B4.10. CHAPTER QUIZZES (Available only in Teaching Package)
- B4.10.1 Quiz 1
- B4.10.2 Quiz 2
- B4.10.3 Quiz 3
- B4.10.4 Quiz 4
- B4.10.5 Quiz 5
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- B6. MOLECULAR DYNAMICS
- B6.1. Introduction
- B6.1.1 What is Molecular Dynamics?
- B6.1.2 Ergodicity Assumption
- B6.1.3 Historical Note
- B6.1.4 Four Types of Applications of MD Simulation
- B6.1.5 Macroscopic Behavior
- B6.1.6 MD Between Experiment and Theory
- B6.1.7 Refinement and Validation of MD
- B6.1.8 Access to Unavailable Data
- B6.1.9 MD Applied to Living Systems
- B6.1.10 Example 1: Relation between Structure and Function
- B6.1.11 Example 2: Relation between Structure and Function
- B6.1.12 Example 3: Relation between Structure and Function
- B6.1.13 Proteins are not Static
- B6.1.14 Thermal Fluctuations
- B6.1.15 Conformational Changes
- B6.1.16 MD as a Way to Study Molecular Motions
- B6.1.17 Mimicking the Way a Molecule Moves
- B6.1.18 Average Properties Derived from MD Trajectories
- B6.1.19 Calculating Molecular Properties of a System
- B6.1.20 Studying Thermodynamic Properties
- B6.1.21 Studying Kinetic Properties
- B6.1.22 Studying Conformational Changes
- B6.2. Energy Calculations
- B6.2.1 Calculation of Forces & Energies
- B6.2.2 Two Families of MD Methods
- B6.2.3 The Quantum Mechanics Approach
- B6.2.4 Quantum Methods are Computationally Expensive
- B6.2.5 The Classical Mechanics Approach
- B6.2.6 Classical vs. Quantum Methods
- B6.2.7 Classical MD Simulates the Dynamics of the Nuclei
- B6.2.8 The Born-Oppenheimer Approximation
- B6.2.9 Force Field for Classical MD
- B6.2.10 General Force Field Equation
- B6.2.11 Stretching Term
- B6.2.12 Bending Term
- B6.2.13 Torsional Term
- B6.2.14 Van der Waals Term
- B6.2.15 Electrostatic Term
- B6.2.16 A Couple of Practical Remarks
- B6.2.17 The Link between Forces and Potential Energies
- B6.3. MD Algorithm
- B6.3.1 Newton's Equation of Motion
- B6.3.2 Prediction of Next Position
- B6.3.3 Integration Step
- B6.3.4 Molecular Dynamics Algorithm
- B6.3.5 Trajectories: List of Positions and Velocities
- B6.3.6 Atomic Positions at Time (t+Δt)
- B6.3.7 Solving Newton's Equations
- B6.3.8 Numerical Integration with the Verlet Formula
- B6.3.9 Summary of the MD Algorithm
- B6.4. Fundamental Issues
- B6.4.1 Time Step
- B6.4.2 Choice of Time Step
- B6.4.3 Time-Scale of Molecular Motions
- B6.4.4 Method for Increasing the Time Step: Constrained MD
- B6.4.5 Periodic Boundary Condition
- B6.4.6 Importance of Long Range Forces
- B6.4.7 The Distance Cutoff Concept
- B6.4.8 Problems with Cutoffs
- B6.4.9 Switching Functions
- B6.4.10 Choice of the Cutoff
- B6.4.11 Strategies to Incorporate the Solvent
- B6.4.12 Implicit Solvent Model
- B6.4.13 Explicit Solvent Molecules
- B6.4.14 The Ewald Summation Method
- B6.5. MD Protocols
- B6.5.1 Typical Steps for MD Simulation
- B6.5.2 Define and Prepare the Molecular System
- B6.5.3 Preparing the Coordinates
- B6.5.4 Manual Assembly of a Complex Molecular System
- B6.5.5 Solvating the System
- B6.5.6 Addition of Counterions
- B6.5.7 Choose the MD Package & Force-Field
- B6.5.8 Extending the Parameterization of the Force Field
- B6.5.9 Configuration Parameters of the MD Simulation
- B6.5.10 Time-step
- B6.5.11 Length of the Simulation
- B6.5.12 Distance Cutoffs
- B6.5.13 Reassigning the List of Non-Bonded Atom Pairs
- B6.5.14 Initial Velocities
- B6.5.15 SHAKE Parameters
- B6.5.16 Preliminary Treatments: Minimization & Equilibration
- B6.5.17 Minimization of Initial Coordinates
- B6.5.18 Thermal Equilibration of the System
- B6.5.19 Maxwell-Boltzmann Equation
- B6.5.20 Molecular Dynamics Run
- B6.5.21 Conservation of the Total Energy
- B6.5.22 Test Energy Fluctuation
- B6.5.23 Possible Crash of the Program
- B6.6. Analysis of the Results of the MD Simulation
- B6.6.1 Analysis of the Results
- B6.6.2 Thermodynamic Properties
- B6.6.3 Kinetic Properties
- B6.6.4 Visualization of Time Dependent Properties
- B6.6.5 Deriving Average Properties from the Trajectory
- B6.6.6 Average Energies
- B6.6.7 Specific Heat
- B6.6.8 Radius of Gyration
- B6.6.9 Local Motions
- B6.6.10 Interesting Motions
- B6.6.11 Movies
- B6.7. Examples of MD Applications
- B6.7.1 First μs MD Simulation of Protein Folding
- B6.7.2 Protein-Folding Dynamics using Folding@Home
- B6.7.3 MD of the Complete Satellite Tobacco Mosaic Virus
- B6.7.4 How Does RNA Moves Along DNA?
- B6.8. Using MD for Conformational Sampling
- B6.8.1 The Sampling Approach in Optimization Problems
- B6.8.2 MD as a Tool for Sampling the Space
- B6.8.3 Sampling to Find the Global Minimum
- B6.8.4 Conformational Analysis of a Small Molecule
- B6.8.5 Conformational Analysis of Biomolecules
- B6.8.6 Loop Conformation in Proteins
- B6.8.7 How Do Ligands and Receptors Bind Together?
- B6.8.8 Protein Folding Problem
- B6.8.9 Systematic and Random Sampling
- B6.8.10 Alternative Methods for Sampling
- B6.8.11 Monte Carlo Random Search
- B6.8.12 Monte Carlo Algorithm
- B6.8.13 Metropolis Monte Carlo Approach
- B6.8.14 Simulated Annealing
- B6.8.15 Diffusion Equation Methods
- B6.8.16 Replica Exchange MD Method
- B6.9. MD for the Calculation of Binding Energies
- B6.9.1 In Silico Drug Design
- B6.9.2 FEP Approach for Calculating Binding Energies
- B6.9.3 FEP Thermodynamic Cycle
- B6.9.4 Exploiting the Thermodynamic Cycle
- B6.9.5 FEP: Computational Alchemy
- B6.9.6 Limitation of FEP Method
- B6.9.7 FEP Study: Example 1
- B6.9.8 FEP Study: Example 2
- B6.10. MD Packages
- B6.10.1 Examples of Popular MD Packages
- B6.10.2 NAMD
- B6.10.3 VMD
- B6.10.4 TINKER
- B6.10.5 AMBER
- B6.10.6 CHARMM
- B6.10.7 GROMACS
- B6.10.8 MOIL
- B6.10.9 GROMOS
- B6.11. Limitations and Perspectives
- B6.11.1 Limitations of MD
- B6.11.2 Error Introduced by Empirical Potentials?
- B6.11.3 Trade Off Between Efficiency and Accuracy
- B6.11.4 Supramolecular Systems
- B6.11.5 Long Range Forces as a Computational Bottleneck
- B6.11.6 Time and Size Limitations
- B6.11.7 Alternative Techniques for Long Time Dynamics
- B6.11.8 From Impossible to Feasible
- B6.11.9 Classical MD is not for Bond Breaking Mechanisms
- B6.11.10 Present and Future
- B6.12. CHAPTER QUIZZES (Available only in Teaching Package)
- B6.12.1 Quiz 1
- B6.12.2 Quiz 2
- B6.12.3 Quiz 3
- B6.12.4 Quiz 4
- B6.12.5 Quiz 5
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