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126 Summary state, we introduce in Chapter 3 a fast and efficient simulation technique, based on the Monte Carlo method, to impose on the bilayer a chosen value of the surface tension, of which the zero value is a particular case. By means of this simulation method we are able to study the area compressibility of the bilayer, and investigate finite-size effects as function of the applied surface tension. We found that for tensionless or stretched bilayers the finite-size effects are very small. Phase behavior of lipid bilayers In Chapter 4 we optimize the model by studying the characteristics of the lipid architecture that are required to correctly reproduce the structural and thermodynamic properties of lipid bilayers. We find that chain stiffness is an important parameter in reproducing the correct density distribution and area dependence on chain length. We find that for single-tail lipids the value of the interaction parameter between the headgroups is a key factor in determining the internal structure of a bilayer. Due to the small hydrophobic section of this lipid model, a large repulsion between the headgroups results in an interdigitated bilayer; interdigitation disappears when the repulsion parameter is decreased. Interdigitated phases are observed experimentally for phospholipids in the gel phase. They do not occur spontaneously, but have to be induced. We propose that the general mechanism that is responsible for inducing interdigitation in a bilayer is a decrease in the interfacial density of the lipid headgroups. We investigate this hypothesis in Chapter 5 where we study the phase diagram of single-tail lipids. We find a fluid and a gel phase for these lipids, and in the gel phase we find a transition from the interdigitated to the non-interdigitated state which is induced by a decrease in the headgroup repulsion. This suggests that it is possible to induce an interdigitated phase in bilayers of single-tail lipids by adding chaotropic salts, which are adsorbed at the bilayer interfacial region and increase the amount of interfacial water. Next we study the phase diagram of double-tail lipids, and in particular of a lipid with five hydrophobic beads in each tail and three hydrophilic head-beads, which can be seen as a coarse-grained representation for the DMPC phospholipid. For this lipid model, we find the phases which are experimentally observed in phosphocholine bilayers. These phases are the low temperature gel phase, or Lβ ′, in which the lipid tails show a tilt respect to the normal to the bilayer plane and have a low diffusion coefficient, and the high temperature fluid phase, or Lα, in which the lipid tails are partially disordered, and the lipids can diffuse in the bilayer plane. Between these two phases we find a narrow region of temperature in which a striated phase is observed, which resembles the ripple, or Pβ ′, phase of the phosphatidylcholine bilayers. By mapping the reduced phase transition temperatures of the simulated system onto the experimental main ( Pβ ′ → Lα) and pre-transition (Lβ ′ → Pβ ′) temperatures for DMPC bilayers, we are able to quantitatively compare bilayer properties like the area per lipid or the bilayer thickness with their experimental values. The very good
agreement we find gives us confidence in the ability of our coarse-grained approach to model real phospholipids systems. Lateral pressure in lipid bilayers While the surface tension of a lipid bilayer, or monolayer, can be measured experimentally, there are no experimental techniques to measure the local distribution of pressure. Simulations can then be an helpful tool to characterize the shape of the pressure profile in lipid bilayers. The study of the effect of local redistribution of lateral pressure in bilayers induced by site dependent changes in the lipid topology can help to answer some important questions. Can shifts in the lateral pressure be induced by changes in the lipid structure, like different level of unsaturation in the chain? How do these changes depend on the position and nature of the modification in the lipid topology? A related and interesting question is the possible correlation between the local distribution of the pressure profile and the partitioning of small molecules in the bilayer: where do small solutes preferentially adsorb in a lipid bilayer? And, is the partitioning of solutes correlated to the distribution of pressure within the bilayer? To address these questions, in Chapter 4 we describe the shape of the lateral pressure distribution in lipid bilayers for different lipid topologies. We show that the pressure distribution is tightly correlated with the density distribution, i.e. with the localization of the lipid segments within the bilayer, while it is less sensitive to the functional form and parameterization of the interaction potentials. To support the latter observation, we compare the pressure profile in a bilayer of coarsegrained double-tail lipids with the pressure profile computed in atomistic molecular dynamics simulations of a DPPC bilayer. We show that the shapes of the pressure profiles calculated with the two different approaches have remarkable similarities. In Chapter 6 we investigate the interaction of small solutes, which can model anesthetics, with the lipid bilayers. We show that the partitioning of small solutes molecules in a bilayer is mainly driven by chemical affinity, i.e. by the degree of hydrophobicity of the solutes. But also another effect is found; these molecules locate preferentially in the region of the bilayer where the pressure profile has local minima. These observations can help to predict the partitioning of molecules like anesthetics in the bilayer. Furthermore, we show that, if the molecules are located in the headgroups region of the bilayer, they significantly decrease the local pressure in this region. Since anesthetics are also incorporated in the bilayer interfacial region, we postulate that these molecules could regulate the activity of membrane proteins trough changes is the pressure distribution. The hydrophobic mismatch In Chapter 7 we extend the coarse-grained model, and apply it to the study of lipid bilayers with embedded proteins, at low protein-to-lipid ratios. In particular we in- 127
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Mesoscopic models of lipid bilayers
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Promotiecommissie: Promotor: • pr
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ii CONTENTS 5.3 Double-tail lipid b
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2 Introduction 1.1 The cell membran
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4 Introduction between the beads, a
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6 Introduction whether the preferre
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8 Simulation method for coarse-grai
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10 Simulation method for coarse-gra
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III Surface tension in lipid bilaye
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3.2 Method of calculation of surfac
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3.2 Method of calculation of surfac
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3.3 Constant surface tension ensemb
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3.3 Constant surface tension ensemb
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3.4 Surface tension in lipid bilaye
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IV Structural characterization of l
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4.2 Structural quantities 39 been r
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4.3 Computational details 41 lipid
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4.4 Results and discussion 43 ρ(z)
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4.4 Results and discussion 45 one l
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4.4 Results and discussion 47 WH HT
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4.4 Results and discussion 49 Shill
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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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Page 87 and 88: 6.2 Computational details 81 For re
Page 89 and 90: 6.3 Results and Discussion 83 withi
Page 91 and 92: 6.3 Results and Discussion 85 ρ(z)
Page 93 and 94: 6.3 Results and Discussion 87 ρ(z)
Page 95 and 96: 6.3 Results and Discussion 89 S m 0
Page 97 and 98: 6.3 Results and Discussion 91 π(z)
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Page 102 and 103: 96 Mesoscopic model for lipid bilay
Page 104 and 105: 98 Mesoscopic model for lipid bilay
Page 106 and 107: 100 Mesoscopic model for lipid bila
Page 125 and 126: References [1] Tanford, C. Science
Page 127 and 128: 7.4 Conclusion 121 [68] Ono, S.; Ko
Page 129 and 130: 7.4 Conclusion 123 [139] Lee, A. Bi
Page 131: Summary Biological membranes, as th
Page 135 and 136: Samenvatting Biologische membranen,
Page 137 and 138: de lage temperatuur gel fase of Lβ
Page 139: ied dat het dichtst bij het hydrofo
Page 143: This thesis is based on the followi
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