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

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4 Introduction between the beads, are called coarse-grain (CG) models. With the coarse-grain approach one can explore longer time and length scales than it is possible by the more traditional atomistic approach. Also, compared to thermodynamic or lattice models for lipid bilayers, CG models retain a number of structural details of the molecular components of the system. In the recent years, CG models have been developed to study biomembrane-like systems at the mesoscopic level, and both MD and Monte Carlo (MC) simulation methods were used on such models [21–25]. However, despite the advantages which arise by minimal modeling in connection with simulation methods like MD and MC, the possibility to study processes that involve the collective behavior of the system is still limited. To try to overcome this limitation, we have used a faster simulation technique, Dissipative Particle Dynamics (DPD) [26–28], on CG models. This approach can be seen as a middle way between the approach based on pseudo three-dimensional models—such as lattice and interfacial models—and the MD on all-atom model approach. 1.3 This thesis The scope of the work presented in this thesis is to develop a CG model for bilayer lipids and molecules interacting with lipid bilayers, and to study the cooperative behavior of these systems. The model is studied by the DPD simulation technique. We start by investigating the structural and thermodynamic properties of the pure lipid systems. We validate the model by comparing the results for model-lipids with those of reconstituted lipid-bilayer systems, which are studied experimentally. Once we have established that the CG model that we have developed is a reliable one to reproduce some key features of a pure lipid bilayer, we proceed by extending the model to the study of bilayers interacting with small solute molecules (which can be considered as a model for anesthetics), and proteins. This thesis is structured as follows. In Chapter 2 we describe the mesoscopic model for lipid bilayers. According to this approach, the lipid molecules are coarse-grained with sets of beads, each of which represents a portion of the molecule. The interactions between the beads are simplified respect to atomistic MD representations, but the molecular nature of the lipid is retained. As an example, in figure 1.2 the chemical structure of the phospholipid dimyristoylphosphatidylcholine (DMPC) and its CG representation are shown. In Chapter 2 we also describe the DPD simulation technique and its application to the CG model. It will be shown that CG lipids spontaneously self-assemble into supramolecular aggregates, like micelles and bilayers. In Chapter 3 we address the debated issue of which is the correct value of the surface tension of simulated lipid bilayers in order to reproduce the structural characteristics of self-assembled, unconstrained membranes, which are known to be in a tensionless state. To this purpose, we introduce a fast and efficient simulation technique, based on the Monte Carlo method, which allows to impose on the bilayer a
1.3 This thesis 5 13 12 11 9 H 10 2 H2 C H C 2 H C H 3 C C 2 H C 2 H2 C H O C 2 H2 C C H2 C C H2 C H2 C O H2 H2 C CH O H2 H3 C C O CH2 C C H2 H2 3 7 8 5 6 4 O P O O 2 C C 1 − H2 N H2 + H2 H2 H2 H2 H2 C C C C C C C C C C H2 H2 H2 H2 O CH3 CH3 CH3 Figure 1.2: The atomistic representation of DMPC and its corresponding coarse-grained model. chosen value of the surface tension, of which the zero value is a particular case. In Chapter 4 the structural properties of the model bilayer, like the bilayer thickness or the area per lipid, are studied in relation to the characteristics of the model lipids. We address the important question of how much chemical detail should—and can—be included in CG models of bilayer lipids. To this purpose, we compare singletail and double-tail model lipids, the latter more closely resembling a real phospholipid, as illustrated in figure 1.2. We show that, depending on the lipid architecture, like stiffness, acyl-chain length, and size of the headgroup, and on the choice of interaction parameters, the model bilayers have different structural characteristics, which we compare with the ones of real phospholipid bilayers. In Chapter 5 we determine the phase diagram of CG lipid bilayers, of both singleand double-tail lipids. By performing simulations in the constant surface tension ensemble, we are able to study structural rearrangements of the bilayer in which the area per lipid changes, and thus directly observe phase transitions. We show that CG single-tail lipids can spontaneously form interdigitated bilayers. In an interdigitated bilayer the two monolayers are not separated, instead the terminal tail groups of the lipids in one monolayer extend further into the bilayer, and face the headgroups of the lipids in the opposing monolayer. Conversely, double-tail lipids, with the appropriate degree of stiffness in the tails, do not spontaneously interdigitate, while they correctly reproduce the gel and fluid phases of lipid bilayers. In Chapter 6 we address the important, and not yet fully understood, problem of the mechanism of action of anesthetics. Whether general anesthetics directly bind to membrane proteins, or act indirectly through changes in the packing properties of the lipid bilayers, is still a matter of debate. An attractive hypothesis was recently proposed by Robert Cantor [29, 30], who described a possible non-specific mechanism to explain the action of anesthetic molecules. Cantor postulated that the activity of anesthetics is lipid-mediated; conformational changes in transmembrane proteins whose functionality is related to depth dependent changes in their cross sectional area might be related to shifts of the lateral pressure profile across the bilayer induced by anesthetic molecules. Experimental measurements of pressure profiles in lipid bilayers are not yet available; on the other hand, pressure profiles can be directly computed in molecular simulations. By means of simulations, we investigate
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 8 and 9: 2 Introduction 1.1 The cell membran
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
Page 59 and 60: 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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