Mesoscopic models of lipid bilayers and bilayers with embedded ...

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2 Introduction 1.1 The cell membrane Cells are the building blocks of every living organism, and the smallest units of life capable of independently sustaining and reproducing themselves. Every cell is a biochemical reaction center, where energy and matter are produced and converted, and where the genetic information is stored. A common structure found in all cells and their inner organelles is the membrane. Biological membranes act as semipermeable barriers, allowing a selected passage of small molecules and ions. Biomembranes are constituted of a lipid matrix in which molecules, such as proteins or cholesterol, are embedded or attached. The lipid matrix is formed by the non-covalent self-assembly of two lipid monolayers made of a variety of lipid types. Lipids are amphiphilic molecules, i.e. molecules constituted of an hydrophilic polar headgroup, which is water soluble, and hydrophobic tails, which are water insoluble. The combination of hydrophobic and hydrophilic groups in the same molecule is a key factor for the assembly of lipids into supra-molecular aggregates, such as micelles or vesicles, the latter being the templates for the cell membranes. Due to the hydrophobic effect [1, 2], membrane lipids assemble in such a way that their hydrophobic part is excluded from a direct contact with the water environment, while the hydrophilic or polar parts are in direct contact with the water. The resulting pseudo two-dimensional system (depicted in figure 1.1) is a fluid structure where the lipids can diffuse in the membrane plane, can flip-flop from one monolayer to another, or may even move out of the system. aqueous environment polar heads hydrocarbon tails Figure 1.1: Schematic representation of a lipid bilayer. Biological membranes are not inert walls, but complex, organized, dynamic, and highly cooperative structures, whose physical properties are important regulators of vital biological functions ranging from cytosis and nerve processes, to transport of energy and matter [3].
1.2 Study of lipid bilayers with computer simulations 3 1.2 Study of lipid bilayers with computer simulations To relate the structure and dynamics of biomembranes to their biological function— the ultimate goal of biomembrane science—it is often necessary to consider simpler systems. Lipid bilayers composed of one or two lipid species, and with embedded proteins or natural or artificial peptides, are often used as model systems. Computer simulations can be used as an approach complementary to experiments for the study of such simplified, soft-condensed matter, systems. Because of the many degrees of freedom involved, the processes that take place even in model biomembranes occur over a wide range of time and length scales [4]. The typical time and length scales of the processes under investigation do pose limitations on the level of chemical and molecular details chosen to represent the model. Often, this necessity follows the fact that some theoretical methods are limited in their applicability by the long computational time needed to calculate statistical quantities. To model membranes, it is thus necessary to decide a priori the level of description of the system, i.e. to neglect those details which are not important to the process one wants to study. Molecular Dynamics (MD) simulation methods on atomistic detailed models have been used to study the structural and dynamic properties of membranes [5], the selfassembly of phospholipids into bilayers [6], as well as the interaction of membrane proteins or other molecules with the lipid bilayer [7–12]. MD simulations can provide detailed information about the phenomena that occur in biomembrane systems at the nanoscopic level and on a nanosecond time-scale. However, many membrane processes happen at the mesoscopic length and time scale, i.e. >1-1000 nm, ns, respectively, and involve the collective nature of the system. This is the case for phase separation, the gel-fluid phase transition, the formation of domains, or the transition from a bilayer to a non-bilayer phase. Even though the speed of numerical computation is increasing very rapidly, it will be some time before it will be possible, by MD on realistic all-atom models, to predict the cooperative behavior of biosystems at mesoscopic time and length scales. An alternative modeling approach consists in neglecting most of the molecular details of the system. The resulting lattice [13, 14], interfacial [15], or phenomenological models [16–18], are computationally very efficient, and can give insight into the physical properties of reconstituted membranes [19, 20]. However, using these models it is difficult to study the structural and conformational properties of the system that derive from some molecular details. To overcome this difficulty, we have developed a model for lipid systems which can be seen as an intermediate between the all-atom models and the models briefly just mentioned. This mesoscopic model considers a system of ‘particles’, or ‘beads’, in which each particle represents a complex molecular component of the system whose details are not important to the process under investigation. These types of models, which use simplified interactions
Page 1: Mesoscopic models of lipid bilayers
Page 4 and 5: Promotiecommissie: Promotor: • pr
Page 6 and 7: ii CONTENTS 5.3 Double-tail lipid b
Page 10 and 11: 4 Introduction between the beads, a
Page 12 and 13: 6 Introduction whether the preferre
Page 14 and 15: 8 Simulation method for coarse-grai
Page 16 and 17: 10 Simulation method for coarse-gra
Page 27 and 28: III Surface tension in lipid bilaye
Page 29 and 30: 3.2 Method of calculation of surfac
Page 31 and 32: 3.2 Method of calculation of surfac
Page 33 and 34: 3.3 Constant surface tension ensemb
Page 35 and 36: 3.3 Constant surface tension ensemb
Page 37 and 38: 3.4 Surface tension in lipid bilaye
Page 43 and 44: IV Structural characterization of l
Page 45 and 46: 4.2 Structural quantities 39 been r
Page 47 and 48: 4.3 Computational details 41 lipid
Page 49 and 50: 4.4 Results and discussion 43 ρ(z)
Page 51 and 52: 4.4 Results and discussion 45 one l
Page 53 and 54: 4.4 Results and discussion 47 WH HT
Page 55 and 56: 4.4 Results and discussion 49 Shill
Page 57 and 58: 4.4 Results and discussion 51 chain
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4.4 Results and discussion 53 4.4.4
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4.4 Results and discussion 55 headg
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58 Phase behavior of coarse-grained
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VI Interaction of small molecules w
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6.2 Computational details 81 For re
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6.3 Results and Discussion 83 withi
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6.3 Results and Discussion 85 ρ(z)
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6.3 Results and Discussion 87 ρ(z)
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6.3 Results and Discussion 89 S m 0
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6.3 Results and Discussion 91 π(z)
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6.3 Results and Discussion 93 the l
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96 Mesoscopic model for lipid bilay
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98 Mesoscopic model for lipid bilay
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100 Mesoscopic model for lipid bila
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References [1] Tanford, C. Science
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7.4 Conclusion 121 [68] Ono, S.; Ko
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7.4 Conclusion 123 [139] Lee, A. Bi
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Summary Biological membranes, as th
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agreement we find gives us confiden
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Samenvatting Biologische membranen,
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de lage temperatuur gel fase of Lβ
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ied dat het dichtst bij het hydrofo
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This thesis is based on the followi
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