Single- and Double-Component Atomistic Models of Phosphatidylcholine Lipid Bilayers in the Gel and Liquid Crystalline Phases Open Access

Abstract

Computational approaches to aggregate systems such as lipid bilayers have come of age. Processor speeds, parallelization and the development of elegant methods has brought into range simulations of systems as large as hundreds of thousands of atoms and timescales into the microsecond regime. With these capabilities, it is increasingly important to develop and qualify good models. This dissertation is divided into three parts, all of which serve to evaluate and refine an atomistic model of phosphatidylcholine lipid bilayers in the gel and/or liquid crystalline phase. In the first part, di-stearoyl-phosphatidylcholine and di-myristoyl-phosphatidylcholine in the gel and LC phases were simulated at a temperature between their experimental main phase transition temperatures Tm,exp. Matched pairs were identified that were in good agreement with experimental systems, and demixing was observed in the gel phase and not in the LC. In the second part, a two-phase system was simulated with a pre-existing interface to probe the phase character over a range of temperatures. DSPC and di-palmitoyl-phosphatidylcholine were simulated at temperatures far below and above the supposed Tm. Both melting and congealing was observed, and rates of transition were used to estimate Tm,virtual's which were within 2% of Tm,exp. Investigation of congealing interfaces revealed that, while tails of lipids deposited onto an existing gel adopt the same tilt angle and direction as the host gel, the glycerol backbones are arranged in a disordered pattern, even if the backbones of the host gel are aligned. This glycerol-backbone orientational disorder has been observed experimentally and is the focus of the next section. Finally, two gels are described and compared, one with disorder in the glycerol-backbone super-lattice, and the other aligned and oriented, like the crystal structure. The backbone-disordered gel is shown to be more like experimental gels structurally and thermodynamically. The structures of gels are shown to be highly influenced by the initial configuration, and the significant effect of backbone arrangement on the overall structure suggests that models of the gel phase should not be based on the crystal structure without regard to defects in the backbone super-lattice.

Table of Contents

List of Tables...vii
List of Figures...viii
References to Previously Published Work...x

1. Introduction...1

1.1 Overview.......................................................................................................1

1.2 Molecular Dynamics .....................................................................................2

1.3 Monte Carlo Methods....................................................................................4

1.4 Molecular Dynamics/ Monte Carol Hybrid Methods......................................5

1.5 Thesis Outline ...............................................................................................5

2. Coexistence of Dimyristoylphosphatidylcholine-Distearoylphosphatidylcholine Gel
and Liquid Crystal Phases...8

2.1 Introduction...................................................................................................8

2.2 Methods ......................................................................................................12


2.2.1 Construction of the DSPC Gel.......................................................12


2.2.2 Construction of the DSPC Liquid Crystal......................................13


2.2.3 Monte Carlo/ Molecular Dynamics ...............................................14

2.3 Results and Discussion ................................................................................15


2.3.1 Pure Bilayer Structures .................................................................15


2.3.2 Semi-Grand Canonical Simulations of DSPC/DMPC Mixtures .....19

2.4 Conclusions.................................................................................................32

3. Determination of Phase Transition Temperatures of Atomistic Model Lipid Bilayers
from Temperature-Dependent Stripe Domain Growth Kinetics...34

3.1 Introduction.................................................................................................34

3.2 Methods ......................................................................................................36


3.2.1 Simulations...................................................................................36


3.2.2 Analysis........................................................................................39

3.3 Results ........................................................................................................40


3.3.1 Lipid Bilayer Annealing................................................................40


3.3.2 Qualitative Analysis of Gel-LC Transition ....................................42


3.3.3 Quantitative Measurement of Domain Growth ..............................45

3.4 Discussion...................................................................................................47

3.5 Conclusions.................................................................................................50

4. An Atomistic Model of the Lβ' Phase of Phosphatidylcholine in the Isothermal-
Isobaric Ensemble...51

4.1 Introduction.................................................................................................51

4.2 Methods ......................................................................................................55


4.2.1 Configuration Construction...........................................................55


4.2.2 Simulations...................................................................................57

4.3 Results and Discussion ................................................................................58


4.3.1 Effect of Backbone Order on Gel Structure ...................................59


4.3.2 Comparison with Previous Simulation Studies ..............................62

4.4 Conclusions.................................................................................................64

References .....................................................................................................................66

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Physical
Keyword	Phase equilibria DPPC Semi-grand canonical ensemble Lipid bilayer simulations DSPC
Committee Chair / Thesis Advisor	Kindt, James, Emory University
Committee Members	Heaven, Michael, Emory University Bowman, Joel M, Emory University

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