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80 Interaction of small molecules with bilayers 6.1 Introduction The role of the pressure profiles in lipid bilayers is an important, and controversial, issue in the study of lipid-protein interactions. Non-bilayer lipids, i.e. lipids which preferentially do not aggregate into a bilayer phase [115], and molecules like alcohols or anesthetics, may alter and shift the distribution of pressure across a bilayer, and in this way the activity of so-called mechanosensitive transmembrane proteins [116] can be regulated. To date, the way anesthetics work is not yet fully understood, and the controversy as to whether the primary mechanism of action of general anesthetics is through a lipid mediated, non-specific, interaction, or via a direct action on the membrane proteins is still a matter of debate (for an exhaustive discussion of the problem see [117] and references therein). An interesting hypothesis was proposed by Cantor [29, 30, 114, 118]. Cantor suggested that a purely mechanical, lipidmediated, effect might be responsible for the action of general anesthetics through an anesthetic-induced redistribution of the lateral pressure across the bilayer. Consider an intrinsic membrane protein that can exist in two principal configurations, of which one is active and the other one inactive. If the two configurations display a different distribution of the cross-sectional area as function of the depth in the bilayer, a redistribution of lateral pressure across the bilayer might shift the conformational equilibria of the protein. In Chapter 3 we have shown that pressure profiles can be directly calculated in molecular simulations, and in Chapter 4 we have discussed how the lipids characteristics, like chain length and stiffness, can determine the distribution of the lateral pressure across a bilayer. In this Chapter we investigate the influence of the bilayer local density and pressure on the partitioning of small, dumb-bell like, solutes in bilayers of lipids with different topology. We also study the modifications induced by the solutes on the bilayer structural properties, and in particular on the distribution of local pressures. 6.2 Computational details A dumb-bell molecule consists of two beads tied together by a harmonic spring. Different chemical properties of these dumb-bells can be represented by varying the strength of the interaction parameters of the dumb-bell beads with the other components of the system, i.e. water and lipids. We consider three types of dumb-bells: purely hydrophobic (indicated in the following as dbH), in which both beads have a large repulsion parameter with water and the lipid headgroup; neutral dumb-bells (dbN), in which both beads interact with the other components as if they were the same specie; and amphiphilic dumb-bells (dbA), in which one bead is hydrophilic and the other one is hydrophobic. The values of the interaction parameters for the different dumb-bells are reported in table 6.1.
6.2 Computational details 81 For reference purpose we also report the interaction parameters between water and lipids. By choosing these three different types of solute molecules we can discriminate between the chemical affinity and the mechanic effects on the distribution of the solutes in the bilayer. dbA dbH dbN a (db1,w) 25 80 25 a (w,w) 25 a (db1,h) 25 80 35 a (w,h) 15 a (db1,t) 50 25 25 a (w,t) 80 a (db2,w) 80 80 25 a (h,h) 35 a (db2,h) 80 80 25 a (h,t) 80 a (db2,t) 25 25 25 a (t,t) 25 a (db1,db1) 25 25 25 a (db2,db2) 25 25 25 a (db1,db2) 25 25 25 Table 6.1: Repulsion parameters aij (for the force of equation F C ij = aij(1−rij/Rc)^rij) between dumb-bells, water, and lipids. Water beads are indicated as w, lipid hydrophilic head-beads as h, lipid hydrophobic tail-beads as t, and the two beads of a dumb-bell as db1 and db2 respectively. Three types of dumb-bells are considered: hydrophobic (dbH), amphiphilic (dbA) and neutral (dbN). To investigate the influence of the lipid characteristics on the distribution of the solutes, we consider three lipid types whose density distribution and lateral pressure profile show different shapes. All the considered lipids have a single tail of 7 hydrophobic beads attached to one hydrophilic head-bead. The lipid tail can have different stiffness. We consider bilayers formed by fully flexible lipids (ht7), by linear, t), and by poly-unsaturated lipids, where the unsaturation points are stiff lipids (ht (L) 6 represented by kinks along the chain (ht (L) t (K) 4 t(L) t). The lipids nomenclature follows the convention introduced in section 4.3 of Chapter 4, and the different lipid topologies used in this work are shown in figure 6.1. In all cases, the solutes were added to equilibrated, tensionless bilayers consisting of 200 lipids (100 in each monolayer), and approximately 2000 water beads, at an overall bead density of 3. The dumb-bells mole fraction (respect to the number of lipids) was 25% (the same used in [119]), which results in 50 dumb-bells for the bilayers considered here. The initial positions of the dumb-bells were chosen at random within the hydrophobic part of the bilayer. The system was then equilibrated for 5000 DPD steps to allow the added molecules to diffuse in the bilayer. After this equilibration period the molecules were already located in the bilayer regions where they would reside throughout the rest of the simulation. Further 20000 MC-DPD cycles with imposed zero surface tension concluded the equilibration. Density and pressure profiles, and bilayer structural characteristics were measured over 50000 MC-DPD cycles (at zero surface tension) with sampling frequency of 10 cycles.
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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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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
Page 61: 4.4 Results and discussion 55 headg
Page 64 and 65: 58 Phase behavior of coarse-grained
Page 85: VI Interaction of small molecules w
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)
Page 99: 6.3 Results and Discussion 93 the l
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 and 132: Summary Biological membranes, as th
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Page 135 and 136: 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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