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Table Of Contents

1.1 Molecular Association
1.2 The Macrobicycle 12 Host-Guest System
1.3 Importance of the Host Binding Properties
1.4 Aim of This Work
2.1 Simulations Methods
2.1.1 The Role of Computer Simulations
2.1.2 Representation of the System
2.1.3 The OPLS Force Field
2.1.4 The System to be Modelled and Other Approxima-
2.1.5 Molecular Dynamics Simulations
2.1.6 Monte Carlo Simulations
2.1.7 Molecular Dynamics Versus Monte Carlo
2.2 Free Energy Methods
2.2.1 The Problem of Calculating Free Energies
2.2.2 Free Energy Perturbation
2.2.3 Thermodynamic Integration
2.2.4 Difficulties With Free Energy Methods
2.2.5 Fast Free Energy Methods
2.2.6 Choice of Free Energy Method
2.3 Applications of Free Energies Methods
2.3.1 Problems Calculating Free Energies of Binding
2.3.2 Relative Free Energies of Binding
2.3.3 Absolute Free Energies of Binding
2.3.4 Previous Studies on Host-Guest Systems
2.3.5 Free Energies of Solvation
2.3.6 Partition Coefficients
2.4 Conclusion
Setup of the Host-Guest System
3.1 Force Field
3.1.1 Missing Parameters from the OPLS Force Field
3.1.2 Transferable Parameters
3.2 Charge Derivation
3.2.1 REPD Charges
3.2.2 Relative Partition Coefficients
3.2.3 Free Energy Protocol
3.2.4 Effect of Basis Set, Ab Initio Method and Geometry
3.3 Dihedral Parameterisation
3.3.1 Calculation of Ab Initio Energy Profile
3.3.2 Fitting a Fourier Series to the Energy Profile
3.3.3 Parameterisation Complications
3.4 Structural Setup
3.4.1 The Z-matrix
3.4.2 Residue Definitions
3.4.3 Residues and Their Application to MC Moves
3.5 Simulation Code Customisation and Optimi-
3.6 Conclusion
Partial Charge Methods
4.1 Partial Charges in Force Fields
4.1.1 The Use of Charges and Methods to Derive Them
4.1.2 Advantages and Disadvantages of OPLS Charges
4.1.3 Advantages and Disadvantages of EPD Charges
4.2 Development of the REPD Charge Method
4.2.1 The EPD Charge Method
4.2.2 Basis Set, Ab Initio Method and Geometry
4.2.3 Fitting Point Method
4.2.4 Multipolar Constraints
4.2.5 Charge Restraining
4.2.6 A New Restraining Function
4.2.7 Choice of Atoms to Restrain
4.2.8 Independenceof the New Restraint On Point Selection
4.2.9 Charge Averaging
4.3 The REPD Charge Method
4.3.1 Summary of the Method
4.3.2 Comparison with EPD and OPLS Charges
4.3.3 Influence of Molecule Set on the Parameterisation
4.3.4 Conformational Dependence
4.4 Conclusion
5.1 FEP Free Energies of Hydration
5.1.1 The Molecule Test Set
5.1.2 Selection of Mutations
5.1.3 Simulation Protocol
5.1.4 Results
5.1.5 Effect of Restraint, Basis Set and Geometry
5.1.6 Particular Discrepancies with Experiment
5.2 LIE Free Energies of Hydration
5.2.1 Form of the LIE Equation
5.2.2 LIE Protocol
5.2.3 Derivation of the LIE Parameters
5.2.4 Performance of LIE Free Energies
5.2.5 Overfitting to the Data
5.2.6 Alternative LIE Functions
5.3 Analysis of the LIE Method
5.3.1 Motivation for the Analysis
5.3.2 Correlation Analysis
5.3.3 Biased Regression Methods
5.3.4 The Most Predictive Model
5.3.5 MLR Versus CR
5.4 Conclusion
6.1 Identification of Sampling Problem
6.1.1 Generation of Possible Host-Guest Structures
6.1.2 Analysis of Annealed Structures
6.1.3 Sampling From Simulations
6.2 Approaches to Improve Sampling
6.2.1 Methods to Improve MC Acceptance
6.2.2 Biased Sampling Methods
6.2.3 More Sophisticated MC Moves
6.2.4 Adoption of Methods to Improve Sampling
6.3 Additional MC Moves
6.3.1 The Conrot Move
6.3.2 Implementation and Testing of the Conrot Move
6.3.3 Application of the Conrot Move to Macrobicycle 12
6.3.4 Acceptance Probability of the Conrot Move
6.4.1 The GB/SA Continuum Model
6.4.2 Requirements for GB/SA
6.4.3 Parameterisation to Poisson-Boltzmann Free Energies
6.4.4 Parameterisation to Experimental Free Energies
6.4.5 Performance of the Derived Parameters
6.5 Sampling of Macrobicycle 12 in Continuum
6.6 Conclusion
7.1 The Macrobicycle 12 System
7.1.1 The Simulation System
7.1.2 Experimental Data
7.1.3 The Role of Computer Simulations
7.2 Explicit Solvent Free Energy Calculations
7.2.1 Gas Phase Simulation Protocol
7.2.2 Explicit Chloroform Protocol
7.2.3 Window Spacing
7.2.6 Host-Guest Free Energies in Explicit Chloroform
7.3 Continuum Solvent Free Energy Calculations
7.3.1 Continuum Chloroform Simulation Protocol
7.3.2 Guest Free Energies in Continuum Chloroform
7.3.3 Host-Guest Free Energies in Continuum Chloroform
7.4 Conclusion
8.1 Description of the Binding Site
8.1.1 Host Binding Features
8.1.2 Guest Binding Features
8.1.3 Origins of Selectivity
8.1.4 The V-Model For Binding
8.2 Guest Orientation
8.3 Hydrogen Bond Analysis
8.3.1 Hydrogen Bond Patterns
8.3.2 Interpretation of Hydrogen Bond Patterns
8.4 Steric Analysis
8.4.1 Extracting Meaningful Steric Information
8.4.2 Probing the Close Contacts for Different Guests
8.4.3 The Nature of the Close Contacts
8.5 Energy Analysis
8.5.1 Energy Components
8.5.2 Interpretation of the Energies
8.6 Conformational Analysis
8.6.1 Variation of Host Shape With Different Guests
8.6.2 Hydrocarbon Chain Conformation
8.6.3 Dominant Hydrocarbon Subconformations
8.6.4 Phenyl Ring Conformation of the Guest
8.7 Rationalisation of Free Energies
8.7.1 Binding Motifs Observed in The Simulations
8.7.2 Connection Between Binding FreeEnergies and Motifs
8.8 Conclusion
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PhD Thesis

PhD Thesis

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Published by Eleonora Santoro

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Published by: Eleonora Santoro on Jun 11, 2012
Copyright:Attribution Non-commercial


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