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A Multi-Scale Molecular Dynamic Approach to the Study of the Outer Membrane of the Bacteria Psudomonas Aeruginosa PA01 and the Biocide Chlorhexidine

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A Multi-Scale Molecular Dynamic Approach to the Study of the Outer Membrane of the Bacteria Psudomonas Aeruginosa PA01 and the Biocide Chlorhexidine A Multi-Scale Molecular Dynamic Approach to the Study of the Outer Membrane of the Bacteria Psudomonas Aeruginosa PA01 and the Biocide Chlorhexidine by Brad Van Oosten B.Sc. (Honours) Department of Physics, Brock University, 2011 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Mathematics and Sciences Department of Physics BROCK UNIVERSITY September 15, 2016 2016 © Brad Van Oosten In presenting this thesis in partial fulfilment of the requirements for an ad- vanced degree at the Brock University, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or pub- lication of this thesis for financial gain shall not be allowed without my written permission. (Signature) Department of Physics Brock University St.Catharines, Canada Date Abstract ii Abstract The introductory chapters of this thesis contains an explanation to the methods and basic theory of the molecular dynamics approach. Together with the ap- pendix section, in which a step by step tutorial how to set up and run basic simulations using the gromacs software is presented, this thesis can serve as an introductory aid in performing molecular dynamics simulations. In the research portion of this thesis, I provide several uses for the molecular dynamics approach applied to the biocide chlorhexidine as well as the study of membranes, including a mimic of the bacteria membrane of Pseudomonas Aeruginosa PA01. The motivation for this research was previous work done in our lab which determined that chlorhexidine has a high affinity for DMPC and found the depth at which it resides in a model DMPC membrane. From this information, an all- atom representation of chlorhexidine was made, which was proven to reproduce the experimental results. While we learned much about chlorhexidine in a model DMPC membrane, this study lacked the destruction of the membrane as well as the study of chlorhexidine in a biologically relevant membrane. For these reasons coarse grained versions of the all-atom chlorhexidine models as well as a new lipopolysaccharide molecule was created. With the coarse grained model of chlorhexidine and the ability to create a bacterial membrane mimic, the study Abstract iii of chlorhexidine and other antibacterial agents can be further studied. Contents iv Contents Abstract ....................................... ii Contents ....................................... iv List of Tables .................................... viii List of Figures .................................... ix Preface ........................................ xiv Acknowledgements ................................ xv 1 Introduction ...................................1 1.1 Molecular Dynamic (MD) Simulations.................1 1.1.1 Quantum Mechanics (QM)...................6 1.1.2 All-Atom (AA)..........................7 1.1.3 Coarse Grained (CG).......................8 1.1.4 Hybrid...............................9 1.2 Force Fields................................ 10 1.2.1 MARTINI............................. 11 Contents v 1.2.2 Slipids............................... 18 1.2.3 Water Models........................... 22 2 Molecular Dynamics .............................. 35 2.1 GROMACS................................. 35 2.2 Energy Minimization (EM)....................... 36 2.3 Molecular Dynamics (MD) Simulation................. 37 2.3.1 Input (Initial Conditions).................... 37 2.3.2 Computing Forces........................ 39 2.3.3 Bonded Potentials........................ 41 2.3.4 Nonbonded Potentials...................... 43 2.3.5 Ensembles............................. 45 2.3.6 Update Configuration and Output............... 47 2.4 Potential of Mean Force (PMF)..................... 47 3 A Molecular Dynamics Study of Chlorhexidine ............. 59 3.1 Introduction................................ 59 3.2 Computational Methods......................... 63 3.3 Results................................... 67 3.4 Discussion................................. 76 4 A MARTINI Extension for LPS ....................... 100 4.1 Introduction................................ 100 4.2 Methods.................................. 103 4.2.1 MARTINI Parameterization................... 103 Contents vi 4.2.2 Membrane Construction..................... 107 4.2.3 Simulation Parameters...................... 109 4.3 Results................................... 110 4.3.1 Bonded Parameters........................ 110 4.3.2 Structural Features........................ 113 4.4 Conclusion................................. 122 4.5 Acknowledgements............................ 124 5 A MARTINI Extension for CHX ....................... 144 5.1 Introduction................................ 144 5.2 MARTINI Parametrization........................ 146 5.3 CHX Parameterization Validation................... 149 5.4 Model Discussion............................. 152 6 Testing High Concentrations of CHX .................... 164 6.1 Introduction................................ 164 6.2 Methods.................................. 166 6.2.1 Simulated Titration........................ 166 6.2.2 Membrane Creation....................... 168 6.2.3 Computational Calorimetry................... 168 6.2.4 MD Simulation Details...................... 169 6.2.5 Weighted Histogram Analysis Method (WHAM)...... 170 6.3 Results................................... 172 6.3.1 CHX Insertion Energetics.................... 172 Contents vii 6.3.2 Membrane Structural Changes................. 175 6.3.3 Calorimetry Method Tests.................... 179 6.3.4 Computational Calorimetry................... 181 6.4 Discussion................................. 183 6.5 Conclusion................................. 185 6.6 Acknowledgements............................ 186 7 Conclusion .................................... 208 8 Future Work ................................... 211 9 Appendicies ................................... 214 9.1 MD Setup and Run Tutorial....................... 214 9.2 Coarse Graining Method Tutorial.................... 219 10 Permissions ................................... 224 List of Tables viii List of Tables 3.1 System Energy Analysis......................... 81 3.2 Simulated Membrane Parameters.................... 82 3.3 Hydrogen Bond Count.......................... 83 4.1 Membrane Physical Properties..................... 137 5.1 CG and AA Computational Cost.................... 160 6.1 PMF Extracted Values.......................... 201 6.2 CHX Insertion Times........................... 202 List of Figures ix List of Figures 1.1 Simulation Time and Size Scales....................4 1.2 Papers Published Using the Martini Force Field........... 16 1.3 Papers Published Using the Slipids Force Field............ 20 1.4 Water Model - Number of Sites..................... 23 1.5 Water Model - Variation Types..................... 24 2.1 Leapfrog Algorithm........................... 40 2.2 Bonded Interactions........................... 42 2.3 PMF Example............................... 51 3.1 Chlorhexidine Grouping Representation................ 84 3.2 Chlorhexidine Depth and Energy Comparison - Inside vs Outside 85 3.3 Chlorhexidine Depth and Energy Comparison - 12 Molecules... 86 3.4 HEX Distributions............................ 87 3.5 CHX:DMPC Neutron Scattering Length Density........... 88 3.6 CHX:DMPC Neutron Scattering Length Density, Simulation vs Ex- periment.................................. 89 3.7 CHX:DMPC Membrane Order Parameter............... 90 List of Figures x 3.8 CHX-DMPC Hydrogen Bonding.................... 91 3.9 Cl-Cl Distance............................... 92 3.10 Chlorhexidine in DMPC Simulation Snapshot............ 93 4.1 Schematic of the Lipopolysaccharide from P. Aeruginosa ...... 125 4.2 AA vs CG Bond Distributions...................... 126 4.3 AA vs CG Angle Distributions..................... 127 4.4 AA vs CG Dihedral Distributions.................... 128 4.5 Symmetric LPS Normalized Number Density............ 129 4.6 Asymmetric LPS Normalized Number Density............ 130 4.7 Terminal Methyl Number Density................... 131 4.8 Water-Ca Ion Radial Distribution Function.............. 132 4.9 CG Lipopolysaccharide Simulation Snapshots............ 133 4.10 Lipopolysaccharide Neutron Scattering Length Density....... 134 4.11 Asymmetric Lipopolysaccharide Area Per Lipid........... 135 4.12 Symmetric Lipopolysaccharide Area Per Lipid............ 136 5.1 CG CHX Mapping and Naming.................... 154 5.2 DMPC and CHX Volume Probabilities................. 155 5.3 CG vs AA Bond Distributions...................... 156 5.4 CG vs AA Angle Distributions..................... 157 5.5 CG vs AA Dihedral Distributions.................... 158 5.6 CG vs AA Cl-Cl Distance........................ 159 6.1 CHX CG Particles............................. 187 List of Figures xi 6.2 CHX PMF - 3 Models........................... 188 6.3 Water PMF................................. 189 6.4 DMPC Spatial Properties at Various CHX Concentrations..... 190 6.5 DMPC Order Parameter at Various CHX Concentrations...... 191 6.6 Time Evolution of CHX Insertion.................... 192 6.7 DMPC and CHX Radial Distribution Function............ 193 6.8 System Properties at Various CHX Concentrations.......... 194 6.9 Specific Heat from Energy........................ 195 6.10 Specific Heat - Time Comparison...................
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