Simulating the effect of alcohol on the structure of a membrane

Adsorption of alcohol molecules or other small amphiphilic molecules in the cell membrane can induce significant changes in the structure of the membrane. To understand the molecular mechanisms underlying these structural changes, we developed a mesoscopic membrane model. Molecular simulations on this model nicely reproduce the experimental phase diagrams. We find that alcohol can induce an interdigitated structure in which the normal bilayer structure changes into a monolayer in which the alcohol molecules screen the hydrophobic tails from the water phase. We compute the effect of the chain length of the alcohol on the phase behaviour of the membrane. At low concentrations of alcohol, the membrane has domains of the interdigitated phase that are in coexistence with the normal membrane phase. We use our model to clarify some of the experimental questions related to the structure of the interdigitated phase and put forward a simple model that explains the alcohol chain length dependence of the stability of this interdigitated phase.     

Membrane models of E. coli containing cyclic moieties in the aliphatic lipid chain

Nearly all molecular dynamics simulations of bacterial membranes simplify the lipid bilayer by composing it of only one or two lipids. Previous attempts of developing a model E. coli membrane have used only 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) POPG lipids. However, an important constituent of bacterial membranes are lipids containing a cyclopropane ring within the acyl chain. We have developed a complex membrane that more accurately reflects the diverse population of lipids within E. coli cytoplasmic membranes, including lipids with a cyclic moiety. Differences between the deuterium order profile of cyclic lipids and monounsaturated lipids are observed. Furthermore, the inclusion of the cyclopropane ring decreases the surface density of the bilayer and produces a more rigid membrane as compared to POPE/POPG membranes. Additionally, the diverse acyl chain length creates a thinner bilayer which matches the hydrophobic thickness of E. coli transmembrane proteins better than the POPE/POPG bilayer. We believe that the complex lipid bilayer more accurately describes a bacterial membrane and suggest the use of it in molecular dynamic simulations rather than simple POPE/POPG membranes.     

Asymmetric glycerophospholipids impart distinctive biophysical properties to lipid bilayers

Phospholipids are a diverse group of biomolecules consisting of a hydrophilic headgroup and two hydrophobic acyl tails. The nature of the head and length and saturation of the acyl tails are important for defining the biophysical properties of lipid bilayers. It has recently been shown that the membranes of certain yeast species contain high levels of unusual asymmetric phospholipids consisting of one long and one medium-chain acyl moiety, a configuration not common in mammalian cells or other well-studied model yeast species. This raises the possibility that structurally asymmetric glycerophospholipids impart distinctive biophysical properties to the yeast membranes. Previously, it has been shown that lipids with asymmetric length tails form a mixed interdigitated gel phase and exhibit unusual endotherm behavior upon heating and cooling. Here, however, we address physiologically relevant temperature conditions and, using atomistic molecular dynamics simulations and environmentally sensitive fluorescent membrane probes, characterize key biophysical parameters (such as lipid packing, diffusion coefficient, membrane thickness, and area per lipid) in membranes composed of both length-asymmetric glycerophospholipids and ergosterol. Interestingly, we show that saturated but asymmetric glycerophospholipids maintain membrane lipid order across a wide range of temperatures. We also show that these asymmetric lipids can substiture of unsaturated symmetric lipids in the phase behaviour of ternary lipid bilayers. This may allow cells to maintain membrane fluidity, even in environments that lack oxygen, which is required for the synthesis of unsaturated lipids and sterols.     

The structure and function of gramicidin A embedded in interdigitated bilayer

The effects of phase transition from normal to interdigitated lipid bilayer on the function and structure of membrane proteins were studied using linear gramicidin (gramicidin A) as a model. Interdigitated bilayer structure of dipalmitoylphosphatidylglycerol (DPPG) liposomes that was induced by atropine could not be changed notably by intercalating of gramicidin. The K+ transportation of gramicidin in both normal and interdigitated bilayer was assayed by measuring the membrane potential. Results showed that gramicidin in interdigitated bilayer exhibited lower transport capability. Intrinsic fluorescence spectrum of gramicidin in interdigitated bilayer blue-shifted 2.8 nm from the spectrum in normal bilayer, which means that interdigitation provides a more hydrophobic environment for gramicidin. Circular dichroism measurement results indicated that the conformation of gramicidin in interdigitated bilayer is not the typical beta6.3 helix as in the normal bilayer. The results suggested that the interdigitated lipid bilayer might largely affect the structure and function of membrane proteins.     

The effect of cholesterol on short- and long-chain monounsaturated lipid bilayers as determined by molecular dynamics simulations and X-ray scattering

We investigate the structure of cholesterol-containing membranes composed of either short-chain (diC14:1PC) or long-chain (diC22:1PC) monounsaturated phospholipids. Bilayer structural information is derived from all-atom molecular dynamics simulations, which are validated via direct comparison to x-ray scattering experiments. We show that the addition of 40 mol % cholesterol results in a nearly identical increase in the thickness of the two different bilayers. In both cases, the chain ordering dominates over the hydrophobic matching between the length of the cholesterol molecule and the hydrocarbon thickness of the bilayer, which one would expect to cause a thinning of the diC22:1PC bilayer. For both bilayers there is substantial headgroup rearrangement for lipids directly in contact with cholesterol, supporting the so-called umbrella model. Importantly, in diC14:1PC bilayers, a dynamic network of hydrogen bonds stabilizes long-lived reorientations of some cholesterol molecules, during which they are found to lie perpendicular to the bilayer normal, deep within the bilayer’s hydrophobic core. Additionally, the simulations show that the diC14:1PC bilayer is significantly more permeable to water. These differences may be correlated with faster cholesterol flip-flop between the leaflets of short-chain lipid bilayers, resulting in an asymmetric distribution of cholesterol molecules. This asymmetry was observed experimentally in a case of unilamellar vesicles (ULVs), and reproduced through a set of novel asymmetric simulations. In contrast to ULVs, experimental data for oriented multilamellar stacks does not show the asymmetry, suggesting that it results from the curvature of the ULV bilayers.     

Robust Driving Forces for Transmembrane Helix Packing

The packing structures of transmembrane helices are traditionally attributed to patterns in residues along the contact surface. In this view, besides keeping the helices confined in the membrane, the bilayer has only a minor effect on the helices structure. Here, we use two different approaches to show that the lipid environment has a crucial effect in determining the cross-angle distribution of packed helices. We analyzed structural data of a membrane proteins database. We show that the distribution of cross angles of helix pairs in this database is statistically indistinguishable from the cross-angle distribution of two noninteracting helices imbedded in the membrane. These results suggest that the cross angle is, to a large extent, determined by the tilt angle of the individual helices. We test this hypothesis using molecular simulations of a coarse-grained model that contains no specific residue interactions. These simulations reproduce the same cross-angle distribution as found in the database. As the tilt angle of a helix is dominated by hydrophobic mismatch between the protein and surrounding lipids, our results indicate that hydrophobic mismatch is the dominant factor guiding the transmembrane helix packing. Other short-range forces might then fine-tune the structure to its final configuration.     

Coarse-grained molecular dynamics simulations of phase transitions in mixed lipid systems containing LPA, DOPA, and DOPE lipids

The mechanisms that mediate biomembrane shape transformations are of considerable interest in cell biology. Recent in vitro experiments show that the chemical transformation of minor membrane lipids can induce dramatic shape changes in biomembranes. Specifically, it was observed that the addition of DOPA to DOPE has no effect on the stability of the bilayer structure of the membrane. In contrast, the addition of LPA to DOPE stabilizes the bilayer phase of DOPE, increasing the temperature of a phase transition from the bilayer to the inverted hexagonal phase. This result suggests that the chemical conversion of DOPA to LPA is sufficient for triggering a dramatic change in the shape of biomembranes. The LPA/DOPA/DOPE mixture of lipids provides a simple model system for understanding the molecular events driving the shape change. In this work, we used coarse-grained molecular dynamics simulations to study the phase transitions of this lipid mixture. We show that despite the simplicity of the coarse-grained model, it reproduces the experimentally observed phase changes of: 1), pure LPA and DOPA with respect to changes in the concentration of cations; and 2), LPA/DOPE and DOPA/DOPE mixtures with respect to temperature. The good agreement between the model and experiments suggests that the computationally inexpensive coarse-grained approach can be used to infer macroscopic membrane properties. Furthermore, analysis of the shape of the lipid molecules demonstrates that the phase behavior of single-lipid systems is consistent with molecular packing theory. However, the phase stability of mixed lipid systems exhibits significant deviations from this theory, which suggests that the elastic energy of the lipids, neglected in the packing theory, plays an important role.     

Stability and membrane orientation of the fukutin transmembrane domain: a combined multiscale molecular dynamics and circular dichroism study

The N-terminal domain of fukutin-I has been implicated in the localization of the protein in the endoplasmic reticulum and Golgi Apparatus. It has been proposed to mediate this through its interaction with the thinner lipid bilayers found in these compartments. Here we have employed multiscale molecular dynamics simulations and circular dichroism spectroscopy to explore the structure, stability, and orientation of the short 36-residue N-terminus of fukutin-I (FK1TMD) in lipids with differing tail lengths. Our results show that FK1TMD adopts a stable helical conformation in phosphatidylcholine lipids when oriented with its principal axis perpendicular to the bilayer plane. The stability of the helix is largely insensitive to the lipid tail length, preventing hydrophobic mismatch by virtue of its mobility and ability to tilt within the lipid bilayers. This suggests that changes in FK1TMD tilt in response to bilayer properties may be implicated in the regulation of its trafficking. Coarse-grained simulations of the complex Golgi membrane suggest the N-terminal domain may induce the formation of microdomains in the surrounding membrane through its preferential interaction with 1,2-dipalmitoyl-sn-glycero-3-phosphatidylinositol 4,5-bisphosphate lipids.     

Influence of hydrophobic mismatch on structures and dynamics of gramicidin a and lipid bilayers

Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4–5 Å from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations—except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water-permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions.     

Penetratin-membrane association: W48/R52/W56 shield the peptide from the aqueous phase

Using molecular dynamics simulations, we studied the mode of association of the cell-penetrating peptide penetratin with both a neutral and a charged bilayer. The results show that the initial peptide-lipid association is a fast process driven by electrostatic interactions. The homogeneous distribution of positively charged residues along the axis of the helical peptide, and especially residues K46, R53, and K57, contribute to the association of the peptide with lipids. The bilayer enhances the stability of the penetratin helix. Oriented parallel to the lipid-water interface, the subsequent insertion of the peptide through the bilayer headgroups is significantly slower. The presence of negatively charged lipids considerably enhances peptide binding. Lateral side-chain motion creates an opening for the helix into the hydrophobic core of the membrane. The peptide aromatic residues form a pi-stacking cluster through W48/R52/W56 and F49/R53, protecting the peptide from the water phase. Interaction with the penetratin peptide has only limited effect on the overall membrane structure, as it affects mainly the conformation of the lipids which interact directly with the peptide. Charge matching locally increases the concentration of negatively charged lipids, lateral lipid diffusion locally decreases. Lipid disorder increases, through decreased order parameters of the lipids interacting with the penetratin side chains. Penetratin molecules at the membrane surface do not seem to aggregate.     

Lipid-protein interactions

Intrinsic membrane proteins are solvated by a shell of lipid molecules interacting with the membrane-penetrating surface of the protein; these lipid molecules are referred to as annular lipids. Lipid molecules are also found bound between transmembrane α-helices; these are referred to as non-annular lipids. Annular lipid binding constants depend on fatty acyl chain length, but the dependence is less than expected from models based on distortion of the lipid bilayer alone. This suggests that hydrophobic matching between a membrane protein and the surrounding lipid bilayer involves some distortion of the transmembrane α-helical bundle found in most membrane proteins, explaining the importance of bilayer thickness for membrane protein function. Annular lipid binding constants also depend on the structure of the polar headgroup region of the lipid, and hotspots for binding anionic lipids have been detected on some membrane proteins; binding of anionic lipid molecules to these hotspots can be functionally important. Binding of anionic lipids to non-annular sites on membrane proteins such as the potassium channel KcsA can also be important for function. It is argued that the packing preferences of the membrane-spanning α-helices in a membrane protein result in a structure that matches nicely with that of the surrounding lipid bilayer, so that lipid and protein can meet without either having to change very much.     

Specific interactions of tryptophan with phosphatidylcholine and digalactosyldiacylglycerol in pure and mixed bilayers in the dry and hydrated state

Amphiphilic solutes play an important role in the desiccation tolerance of plant cells, because they can reversibly partition into cellular membranes during dehydration. Their effects on membrane stability depend on their chemical structure, but also on the lipid composition of the host membrane. We have shown recently that tryptophan destabilizes liposomes during freezing. The degree of destabilization depends on the presence of glycolipids in the membranes, but not on the phase preference (bilayer or non-bilayer) of the lipids in mixtures with the bilayer lipid phosphatidylcholine. Here, we have investigated the influence of tryptophan on the phase behavior and intermolecular interactions in dry and hydrated bilayers made from the phospholipid egg phosphatidylcholine and the plant chloroplast glycolipid digalactosyldiacylglycerol, or from a mixture (1:1) of these lipids, using Fourier-transform infrared spectroscopy. To distinguish effects of the hydrophobic ring structure of tryptophan from those of the amino acid moiety, we also performed experiments with the hydrophilic amino acid glycine. Our data show that there are specific interactions between tryptophan and either phospholipid or glycolipid in the dry state, as well as H-bonding interactions between the lipids and both solutes. In the rehydrated state, the H-bonding interactions between amino acids and lipids are mostly replaced by interactions between water and lipids, while the hydrophobic interactions between lipids and tryptophan mostly persist.     

Interdigitated structure of phospholipid-alcohol systems studied by x-ray diffraction.

In the interdigitated structure of phosphatidylcholine/alcohol systems, the one-dimensional electron density profile in the direction normal to the membrane surface is generated from the x-ray diffraction pattern. The membrane thickness for these systems is expressed by the sum of the hydrocarbon chain lengths of phosphatidylcholine and alcohol molecules. For this study, various sets of phosphatidylcholines and 1-alcohols were used; a phosphatidylcholine has a carbon number from 14 to 18 in a hydrocarbon chain, and an alcohol has a carbon number from 1 (methanol) to 4 (1-butanol). Based upon the results, we propose a model for the interdigitated structure in which 1) two alcohol molecules occupy a volume whose surface is surrounded interstitially by the headgroups of phosphatidylcholine molecules, and 2) the methyl ends of both hydrocarbon chains in alcohol and phosphatidylcholine molecules face each other at the bottom of the volume.     

The influence of proteins and peptides on the phase properties of lipids

This paper reviews model membrane studies on the modulation of the macroscopic structure of lipids by lipid-protein interactions, with particular emphasis on the gramicidin molecule. This hydrophobic peptide has three main effects on lipid polymorphism: (1) in lysophosphatidylcholine it triggers a micellar to bilayer transition, (2) in phosphatidylethanolamine it lowers the bilayer to hexagonal H_II phase transition temperature and (3) in phosphatidylcholine and other bilayer preferring lipids it is able to induce the formation of an H_II phase. From experiments in which the gramicidin molecule was chemically modified it can be concluded that the tryptophan residues play a determining role in the peptide-induced changes in polymorphism. The experimental data lead to the proposal that gramicidin molecules have a tendency to self-associate, possibly mediated by tryptophan-tryptophan interactions and organize into tubular structures such as found in the H_II phase.     

Studies of mixed-chain diacyl phosphatidylcholines with highly asymmetric acyl chains: a Fourier transform infrared spectroscopic study of interfacial hydration and hydrocarbon chain packing in the mixed interdigitated gel phase.

The mixed interdigitated gel phases of unlabeled, specifically 13C = O-labeled, and specifically chain-perdeuterated samples of 1-O-eicosanoyl, 2-O-lauroyl phosphatidylcholine and 1-O-decanoyl, 2-O-docosanoyl phosphatidylcholine were studied by infrared spectroscopy. Our results suggest that at the liquid-crystalline/gel phase transition temperatures of these lipids, there is a greater redistribution in the populations of free and hydrogen-bonded ester carbonyl groups than is commonly observed with symmetric chain n-saturated diacyl phosphatidylcholines. The formation of the mixed interdigitated gel phase coincides with the appearance of a marked asymmetry in the contours of the C = O stretching band, a process which becomes more pronounced as the temperature is reduced. This asymmetry is ascribed to the emergence of a predominant lipid population consisting of free sn1- and hydrogen-bonded (hydrated) sn2-ester carbonyl groups. This suggests that the region of the mixed interdigitated bilayer polar/apolar interface near to the sn1-ester carbonyl group is less hydrated than is the case with the noninterdigitated gel-phase bilayers formed by normal symmetric chain phosphatidylcholines. In the methylene deformation region of the spectrum, the unlabeled lipids exhibit a pronounced splitting of the CH2 scissoring bands. This splitting is significantly attenuated when the short chains are perdeuterated and collapses completely upon perdeuteration of the long chains, irrespective of whether the long (or short) chains are esterified to the sn1 or sn2 positions of the glycerol backbone. These results are consistent with a global hydrocarbon chain packing motif in which the zigzag planes of the hydrocarbon chains are perpendicular to each other and the sites occupied by long chains are twice as numerous as those occupied by short chains. The experimental support for this chain-packing motif enabled more detailed considerations of the possible ways in which these lipid molecules are assembled in the mixed interdigitated gel phase. Generally, our results are compatible with a previously proposed model in which the mixed interdigitated gel phase is an assembly of repeat units which consists of two phosphatidylcholine molecules forming a triple-chain structure with the long chains traversing the bilayer and with the methyl termini of the shorter chains opposed at the bilayer center. Our data also suggest that the packing format which is most consistent with our results and previously published work is one in which the hydrocarbon chains of each repeat unit are parallel to each other with the repeat units themselves being perpendicularly packed.     

Membrane hydrophobicity determines the activation free energy of passive lipid transport

The collective behavior of lipids with diverse chemical and physical features determines a membrane’s thermodynamic properties. Yet, the influence of lipid physicochemical properties on lipid dynamics, in particular interbilayer transport, remains underexplored. Here, we systematically investigate how the activation free energy of passive lipid transport depends on lipid chemistry and membrane phase. Through all-atom molecular dynamics simulations of 11 chemically distinct glycerophospholipids, we determine how lipid acyl chain length, unsaturation, and headgroup influence the free energy barriers for two elementary steps of lipid transport: lipid desorption, which is rate limiting, and lipid insertion into a membrane. Consistent with previous experimental measurements, we find that lipids with longer, saturated acyl chains have increased activation free energies compared to lipids with shorter, unsaturated chains. Lipids with different headgroups exhibit a range of activation free energies; however, no clear trend based solely on chemical structure can be identified, mirroring difficulties in the interpretation of previous experimental results. Compared to liquid-crystalline phase membranes, gel phase membranes exhibit substantially increased free energy barriers. Overall, we find that the activation free energy depends on a lipid’s local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membrane’s interfacial hydrophobicity. Both of these properties can be altered through changes in lipid acyl chain length, lipid headgroup, and membrane phase. Thus, the rate of lipid transport can be tuned through subtle changes in local membrane composition and order, suggesting an unappreciated role for nanoscale membrane domains in regulating cellular lipid dynamics.     

Dependence of lipid chain and head group packing of the inverted hexagonal phase on hydration

A model which positions the hydrophobic/hydrophilic boundary in phosphatidylethanolamine lipids at the first CH₂ group in the acyl or alkyl chain is used to calculate the surface area per lipid, the mean chain and head-group dimensions and diameters of the hydrophilic tubes of the inverted hexagonal phase of didodecylphosphatidylethanolamine. The calculated surface areas compare favorably with areas obtained for the lamellar liquid crystal phase of the same lipid using the same boundary. Placement of the boundary within the lipid structure permits a determination of the maximum headgroup packing at hydration levels down to complete dehydration. The headgroup dimensions are consistent with a 5 Å diam void at the center of a hydrophilic tube at zero hydration. The calculated mean fluid chain length is ~2 Å smaller than the mean chain length of the lamellar phase at comparable levels of hydration. Comparison of the calculated mean fluid chain length and distances between hydrophobic boundaries shows that the fluid chains are interdigitated between adjacent tubes, and not interdigitated in the central space between three tubes. At low hydration the chains interdigitate in both spaces. The number of lipids packed around a tube at low hydration is only a function of the headgroup geometry, whereas at high hydration, it is a function of the number of carbon atoms in the chains.     

Molecular theory of lipid-protein interaction and the Lalpha-HII transition.

We present a molecular-level theory for lipid-protein interaction and apply it to the study of lipid-mediated interactions between proteins and the protein-induced transition from the planar bilayer (Lalpha) to the inverse-hexagonal (HII) phase. The proteins are treated as rigid, membrane-spanning, hydrophobic inclusions of different size and shape, e.g., "cylinder-like," "barrel-like," or "vase-like." We assume strong hydrophobic coupling between the protein and its neighbor lipids. This means that, if necessary, the flexible lipid chains surrounding the protein will stretch, compress, and/or tilt to bridge the hydrophobic thickness mismatch between the protein and the unperturbed bilayer. The system free energy is expressed as an integral over local molecular contributions, the latter accounting for interheadgroup repulsion, hydrocarbon-water surface energy, and chain stretching-tilting effects. We show that the molecular interaction constants are intimately related to familiar elastic (continuum) characteristics of the membrane, such as the bending rigidity and spontaneous curvature, as well as to the less familiar tilt modulus. The equilibrium configuration of the membrane is determined by minimizing the free energy functional, subject to boundary conditions dictated by the size, shape, and spatial distribution of inclusions. A similar procedure is used to calculate the free energy and structure of peptide-free and peptide-rich hexagonal phases. Two degrees of freedom are involved in the variational minimization procedure: the local length and local tilt angle of the lipid chains. The inclusion of chain tilt is particularly important for studying noncylindrical (for instance, barrel-like) inclusions and analyzing the structure of the HII lipid phase; e.g., we find that chain tilt relaxation implies strong faceting of the lipid monolayers in the hexagonal phase. Consistent with experiment, we find that only short peptides (large negative mismatch) can induce the Lalpha --> HII transition. At the transition, a peptide-poor Lalpha phase coexists with a peptide-rich HII phase.     

Is the protein/lipid hydrophobic matching principle relevant to membrane organization and functions?

Biological membranes are complex and well-organized multimolecular assemblies composed of a wide variety of protein and lipid molecular species. If such a diversity in protein and lipid polar headgroup structures may easily be related to a large panel of functions, the wide dispersion in acyl chain length and structure which the lipids display is more difficult to understand. It is not required for maintaining bilayer assembly and fluidity. Direct information on the lateral distribution of these various molecular species, on their potential specificity for interaction between themselves and with proteins and on the functional implications of these interactions is also still lacking. Because hydrophobic interactions play a major role in stabilizing membrane structures, we suggest considering the problem from the point of view of the matching of the hydrophobic surface of proteins by the acyl chains of the lipids. After a brief introduction to the hydrophobic matching principle, we will present experimental results which demonstrate the predictive power of the current theories and then, we will introduce the new and important concept of protein/lipid sorting in membranes. Finally, we will show how the hydrophobic matching condition may play a key role in the membrane organization and function.     

Stability of a melittin pore in a lipid bilayer: a molecular dynamics study

We have investigated the configuration and the stability of a single membrane pore bound by four melittin molecules and embedded in a fully hydrated bilayer lipid membrane. We used molecular dynamics simulations up to 5.8 ns. It is found that the initial tetrameric configuration decays with increasing time into a stable trimer and one monomer. This continuous transformation is accompanied by a lateral expansion of the aqueous pore exhibiting a final size comparable to experimental findings. The expansion-induced formation of an interface between the pore-lining acyl chains of the lipids and the pore water ("hydrophobic pore") is transformed into an energetically more favorable toroidal pore structure where some lipid heads are translocated from the rim to the central part of the interface ("hydrophilic pore"). The expansion of the pore is supported by the electrostatic repulsion among the alpha-helices. It is hypothesized that pore growth, and hence cell lysis, is induced by a melittin-mediated line tension of the pore.