Distribution of Pentachlorophenol in Phospholipid Bilayers: A Molecular Dynamics Study

Molecular dynamics computer simulations of pentachlorophenol (PCP) in palmitoyl-oleoyl-phosphatidylethanolamine and palmitoyl-oleoyl-phosphatidylcholine lipid bilayers were carried out to investigate the distribution of PCP and the effects of PCP on the phospholipid bilayer structure. Starting from two extreme starting structures, including PCP molecules outside the lipid bilayer, the PCP distribution converges in simulations of up to 50 ns. PCP preferentially occupies the region between the carbonyl groups and the double bonds in the acyl chains of the lipid molecules in the bilayer. In the presence of PCP, the lipid chain order increases somewhat in both chains, and the average tilt angle of the lipid chains decreases. The increase in the lipid chain order in the presence of PCP was more pronounced in the palmitoyl-oleoyl-phosphatidylcholine bilayer compared to the palmitoyl-oleoyl-phosphatidylethanolamine bilayer. The number of trans conformations of lipid chain dihedrals does not change significantly. PCP aligns parallel to the alkyl chains of the lipid to optimize the packing in the dense ordered chain region of the bilayer. The hydroxyl group of PCP forms hydrogen bonds with both water and lipid oxygen atoms in the water/lipid interface region.     

Insertion of externally administered amyloid beta peptide 25-35 and perturbation of lipid bilayers

To understand the molecular basis and to prevent diseases such as Alzheimer's disease (AD), the targets of the triggering agent have to be elucidated. beta-Amyloid peptide (Abeta) is the major component of extracellular senile plaques characteristic of AD. For a very long time, the aggregated form of the Abeta was supposed to be responsible for the neurodegeneration that occurs in AD. Recently, the attention has been diverted to the monomeric or oligomeric forms of Abeta and their interaction with cellular targets. In our investigation, the physiological and medically important insertion of externally applied Abeta monomers into the bilayer of lipid vesicles is demonstrated. Abeta(25-35) has been localized in the region of the lipid alkyl chain, and it has a severe disordering effect on the lamellar order of the lipid bilayer. Both of these results are of biomedical relevance.     

Studying the structure of single-component ceramide bilayers with molecular dynamics simulations using different force fields

Molecular dynamics simulations are performed on a lipid bilayer that consists of ceramide NS 24:0 in an attempt to examine several structural and physicochemical properties of the specific system. The simulations are carried out with five different force fields (OPLS, GROMOS, BERGER, CHARMM and GAFF) in order to evaluate and compare their performance in modelling lipid systems that contain ceramides. The examined properties include bilayer thickness, chain tilt, density profiles, order parameters, chain conformation, area per lipid and (intermolecular or intramolecular) hydrogen bonding between the head groups. Special focus is given to the lateral lipid arrangement. To this purpose, a method is proposed that utilises the radial distribution functions of the alkyl chains to derive quantitative information about the lateral lipid packing. In most cases, all force fields lead to similar results. For a few properties (e.g. intramolecular hydrogen bonding), there is some discrepancy between the force fields but the lack of respective experimental data does not allow an unambiguous conclusion on which force field is the most reliable.     

How to lose a kink and gain a helix: pH independent conformational changes of the fusion domains from influenza hemagglutinin in heterogeneous lipid bilayers

We have simulated two conformations of the fusion domain of influenza hemagglutinin (HA) within explicit water, salt, and heterogeneous lipid bilayers composed of POPC:POPG (4:1). Each conformation has seven different starting points in which the initial peptide structure is the same for each conformation, but the location across the membrane normal and lipid arrangement around the peptide are varied, giving a combined total simulation time of 140 ns. For the HA5 conformation (primary structure from recent NMR spectroscopy at pH = 5), the peptide exhibits a stable and less kinked structure in the lipid bilayer compared to that from the NMR studies. The relative fusogenic behavior of the different conformations has been investigated by calculation of the relative free energy of insertion into the hydrophobic region of lipid bilayer as a function of the depth of immersion. For the HA7 conformations (primary structure from recent NMR spectroscopy at pH = 7.4), while the N-terminal helix preserves its initial structure, the flexible C-terminal chain produces a transient helical motif inside the lipid bilayer. This conformational change is pH-independent, and is closely related to the peptide insertion into the lipid bilayer.     

Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl

Two 40 ns molecular dynamics simulations of a palmitoyl-oleoyl phosphatidylserine (POPS) lipid bilayer in the liquid crystalline phase with Na(+) counterions and NaCl were carried out to investigate the structure of the negatively charged lipid bilayer and the effect of salt (NaCl) on the lipid bilayer structure. Na(+) ions were found to penetrate deep into the ester region of the water/lipid interface of the bilayer. Interaction of the Na(+) ions with the lipid bilayer is accompanied by a loss of water molecules around the ion and a simultaneous increase in the number of ester carbonyl oxygen atoms binding the ion, which define an octahedral and square pyramidal geometry. The amine group of the lipid molecule is involved in the formation of inter- and intramolecular hydrogen bonds with the carboxylate and the phosphodiester groups of the lipid molecule. The area per lipid of the POPS bilayer is unaffected by the presence of 0.15M NaCl. There is a small increase in the order parameter of carbon atoms in the beginning of the alkyl chain in the presence of NaCl. This is due to a greater number of Na(+) ions being coordinated by the ester carbonyl oxygen atoms in the water/lipid interface region of the POPS bilayer.     

Structure and dynamics of the dilauroylphosphatidylethanolamine lipid bilayer.

A 200-ps molecular dynamics (MD) simulation trajectory of a model dilauroylphosphatidylethanolamine (DLPE) bilayer in water at 315 K has been generated. Segmental order parameters, electron density profiles, and water pair distribution functions have been calculated. Comparison to experiment is made where possible. The dynamics of the system has been studied by analyzing the velocity autocorrelation functions (VAF) of both water and lipid atoms. Furthermore, the diffusive properties of water have been analyzed by computing the mean square displacement (MSD) and orientational correlation function (OCF) of water in two regions around the bilayer. The calculated order parameters show a behavior similar to the liquid crystalline phase of other bilayers, but the region around C1-C3 does not show the expected behavior. The electron density profile shows features that are characteristic of the liquid crystalline phase. The radial distribution functions suggest ordering of water near the charged head groups, which results in about 15 water molecules solvating each lipid molecule. We find from the VAF, MSD, and OCF calculation that the water molecules near the head groups of the lipid bilayer move more slowly than those further away. The VAF of the hydrocarbon chains have features of low-frequency motions that are probably cooperative nature in addition to the high-frequency motions associated with bond angle and torsional motions.     

Interactions of the M2delta segment of the acetylcholine receptor with lipid bilayers: a continuum-solvent model study

M2delta, one of the transmembrane segments of the nicotinic acetylcholine receptor, is a 23-amino-acid peptide, frequently used as a model for peptide-membrane interactions. In this and the companion article we describe studies of M2delta-membrane interactions, using two different computational approaches. In the present work, we used continuum-solvent model calculations to investigate key thermodynamic aspects of its interactions with lipid bilayers. M2delta was represented in atomic detail and the bilayer was represented as a hydrophobic slab embedded in a structureless aqueous phase. Our calculations show that the transmembrane orientation is the most favorable orientation of the peptide in the bilayer, in good agreement with both experimental and computational data. Moreover, our calculations produced the free energy of association of M2delta with the lipid bilayer, which, to our knowledge, has not been reported to date. The calculations included 10 structures of M2delta, determined by nuclear magnetic resonance in dodecylphosphocholine micelles. All the structures were found to be stable inside the lipid bilayer, although their water-to-membrane transfer free energies differed by as much as 12 kT. Although most of the structures were roughly linear, a single structure had a kink in its central region. Interestingly, this structure was found to be the most stable inside the lipid bilayer, in agreement with molecular dynamics simulations of the peptide and with the recently determined structure of the intact receptor. Our analysis showed that the kink reduced the polarity of the peptide in its central region by allowing the electrostatic masking of the Gln13 side chain in that area. Our calculations also showed a tendency for the membrane to deform in response to peptide insertion, as has been previously found for the membrane-active peptides alamethicin and gramicidin. The results are compared to Monte Carlo simulations of the peptide-membrane system, as presented in the accompanying article.     

Site-specific deuterium order parameters and membrane-bound behavior of a peptide fragment from the intracellular domain of HIV-1 gp41.

The behavior of the cytolytic peptide fragment 828-848 (P828) from the carboxy-terminus of the envelope glycoprotein gp41 of HIV-1 in membranes was investigated by solid-state 2H NMR on P828 with the selectively deuterated isoleucines I3, I13, I16, and I20. The quadrupole splittings of the I3 side chain show significant sensitivity to the main phase-transition temperature of the lipid, consistent with partial penetration of the N-terminal peptide region into the hydrophobic core of the membrane. In contrast, the quadrupole splittings of I13, I16, and I20 are in agreement with a location of the C-terminal portion of the peptide near the lipid/water interface. The perturbation of the bilayer by the peptide was studied by 2H NMR on sn-1 chain deuterated 1-stearoyl-2-oleoyl-sn-glycero-3-phosphoserine membranes. Peptide incorporation results in a significant reduction of lipid chain order toward the bilayer center, but only a modest reduction near the lipid glycerol. These observations suggest a penetration of the partially structured peptide backbone into the membrane/water interface region that reduces lateral packing density and decreases order in the hydrophobic core. In addition, the structure of the peptide was investigated free in water and bound to SDS micelles by high-resolution NMR. P828 is unstructured in water but exists in a flexible partially helical conformation when bound to negatively charged liposomes or micelles. The flexible helix covers the first 14 residues of the peptide, whereas the C-terminus of the peptide, where three of the six positively charged arginine residues are located, appears to be unstructured. The peptide-induced changes in lipid chain order profiles indicate that membrane curvature stress is the driving force for the cytolytic behavior of P828.     

Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer.

We report a constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal (L alpha) phase bilayer of dipalmitoylphosphatidylcholine at 50 degrees C and 28 water molecules/lipid. We have shown that the bilayer is stable throughout the 1550-ps simulation and have demonstrated convergence of the system dimensions. Several important aspects of the bilayer structure have been investigated and compared favorably with experimental results. For example, the average positions of specific carbon atoms along the bilayer normal agree well with neutron diffraction data, and the electron density profile is in accord with x-ray diffraction results. The hydrocarbon chain deuterium order parameters agree reasonably well with NMR results for the middles of the chains, but the simulation predicts too much order at the chain ends. In spite of the deviations in the order parameters, the hydrocarbon chain packing density appears to be essentially correct, inasmuch as the area/lipid and bilayer thickness are in agreement with the most refined experimental estimates. The deuterium order parameters for the glycerol and choline groups, as well as the phosphorus chemical shift anisotropy, are in qualitative agreement with those extracted from NMR measurements.     

Phase behavior and nanoscale structure of phospholipid membranes incorporated with acylated C14-peptides

The thermotropic phase behavior and lateral structure of dipalmitoylphosphatidylcholine (DPPC) lipid bilayers containing an acylated peptide has been characterized by differential scanning calorimetry (DSC) on vesicles and atomic force microscopy (AFM) on mica-supported bilayers. The acylated peptide, which is a synthetic decapeptide N-terminally linked to a C14 acyl chain (C14-peptide), is incorporated into DPPC bilayers in amounts ranging from 0-20 mol %. The calorimetric scans of the two-component system demonstrate a distinct influence of the C14-peptide on the lipid bilayer thermodynamics. This is manifested as a concentration-dependent downshift of both the main phase transition and the pretransition. In addition, the main phase transition peak is significantly broadened, indicating phase coexistence. In the AFM imaging scans we found that the C14-peptide, when added to supported gel phase DPPC bilayers, inserts preferentially into preexisting defect regions and has a noticeable influence on the organization of the surrounding lipids. The presence of the C14-peptide gives rise to a laterally heterogeneous bilayer structure with coexisting lipid domains characterized by a 10 A height difference. The AFM images also show that the appearance of the ripple phase of the DPPC lipid bilayers is unaffected by the C14-peptide. The experimental results are supported by molecular dynamics simulations, which show that the C14-peptide has a disordering effect on the lipid acyl chains and causes a lateral expansion of the lipid bilayer. These effects are most pronounced for gel-like bilayer structures and support the observed downshift in the phase-transition temperature. Moreover, the molecular dynamics data indicate a tendency of a tryptophan residue in the peptide sequence to position itself in the bilayer headgroup region.     

Structure, topology, and tilt of cell-signaling peptides containing nuclear localization sequences in membrane bilayers determined by solid-state NMR and molecular dynamics simulation studies

Cell-signaling peptides have been extensively used to transport functional molecules across the plasma membrane into living cells. These peptides consist of a hydrophobic sequence and a cationic nuclear localization sequence (NLS). It has been assumed that the hydrophobic region penetrates the hydrophobic lipid bilayer and delivers the NLS inside the cell. To better understand the transport mechanism of these peptides, in this study, we investigated the structure, orientation, tilt of the peptide relative to the bilayer normal, and the membrane interaction of two cell-signaling peptides, SA and SKP. Results from CD and solid-state NMR experiments combined with molecular dynamics simulations suggest that the hydrophobic region is helical and has a transmembrane orientation with the helical axis tilted away from the bilayer normal. The influence of the hydrophobic mismatch, between the hydrophobic length of the peptide and the hydrophobic thickness of the bilayer, on the tilt angle of the peptides was investigated using thicker POPC and thinner DMPC bilayers. NMR experiments showed that the hydrophobic domain of each peptide has a tilt angle of 15 +/- 3 degrees in POPC, whereas in DMPC, 25 +/- 3 degree and 30 +/- 3 degree tilts were observed for SA and SKP peptides, respectively. These results are in good agreement with molecular dynamics simulations, which predict a tilt angle of 13.3 degrees (SA in POPC), 16.4 degrees (SKP in POPC), 22.3 degrees (SA in DMPC), and 31.7 degrees (SKP in DMPC). These results and simulations on the hydrophobic fragment of SA or SKP suggest that the tilt of helices increases with a decrease in bilayer thickness without changing the phase, order, and structure of the lipid bilayers.     

Structure and dynamics of the lipid modifications of a transmembrane α-helical peptide determined by ²H solid-state NMR spectroscopy

The fusion of biological membranes is mediated by integral membrane proteins with α-helical transmembrane segments. Additionally, those proteins are often modified by the covalent attachment of hydrocarbon chains. Previously, a series of de novo designed α-helical peptides with mixed Leu/Val sequences was presented, mimicking fusiogenically active transmembrane segments in model membranes (Hofmann et al., Proc. Natl. Acad. Sci. USA 101 (2004) 14776-14781). From this series, we have investigated the peptide LV16 (KKKW LVLV LVLV LVLV LVLV KKK), which was synthesized featuring either a free N-terminus or a saturated N-acylation of 2, 8, 12, or 16 carbons. We used 2H and 31P NMR spectroscopy to investigate the structure and dynamics of those peptide lipid modifications in POPC and DLPC bilayers and compared them to the hydrocarbon chains of the surrounding membrane. Except for the C2 chain, all peptide acyl chains were found to insert well into the membrane. This can be explained by the high local lipid concentrations the N-terminal lipid chains experience. Further, the insertion of these peptides did not influence the membrane structure and dynamics as seen from the 2H and 31P NMR data. In spite of the fact that the longer acyl chains insert into the membrane, they do not adapt their lengths to the thickness of the bilayer. Even the C16 lipid chain on the peptide, which could match the length of the POPC palmitoyl chain, exhibited lower order parameters in the upper chain, which get closer and finally reach similar values in the lower chain region. 2H NMR square law plots reveal motions of slightly larger amplitudes for the peptide lipid chains compared to the surrounding phospholipids. In spite of the significantly different chain lengths of the acylations, the fraction of gauche defects in the inserted chains is constant.     

Transmembrane helix structure, dynamics, and interactions: multi-nanosecond molecular dynamics simulations.

To probe the fundamentals of membrane/protein interactions, all-atom multi-nanosecond molecular dynamics simulations were conducted on a single transmembrane poly(32)alanine helix in a fully solvated dimyristoyphosphatidylcholine (DMPC) bilayer. The central 12 residues, which interact only with the lipid hydrocarbon chains, maintained a very stable helical structure. Helical regions extended beyond these central 12 residues, but interactions with the lipid fatty-acyl ester linkages, the lipid headgroups, and water molecules made the helix less stable in this region. The C and N termini, exposed largely to water, existed as random coils. As a whole, the helix tilted substantially, from perpendicular to the bilayer plane (0 degree) to a 30 degrees tilt. The helix experienced a bend at its middle, and the two halves of the helix at times assumed substantially different tilts. Frequent hydrogen bonding, of up to 0.7 ns in duration, occurred between peptide and lipid molecules. This resulted in correlated translational diffusion between the helix and a few lipid molecules. Because of the large variation in lipid conformation, the lipid environment of the peptide was not well defined in terms of "annular" lipids and on average consisted of 18 lipid molecules. When compared with a "neat" bilayer without peptide, no significant difference was seen in the bilayer thickness, lipid conformations or diffusion, or headgroup orientation. However, the lipid hydrocarbon chain order parameters showed a significant decrease in order, especially in those methylene groups closest to the headgroup.     

Fluorescence analysis of tryptophan-containing variants of the LamB signal sequence upon insertion into a lipid bilayer

To investigate the interaction of the LamB signal sequence with lipid bilayers, we have synthesized three tryptophan-containing analogues of the wild-type signal peptide. The tryptophan residues were used as intrinsic fluorescent probes of the N-terminal (position 5), central (position 18), and C-terminal (position 24) regions of the 25-residue peptide. The tryptophan substitutions did not significantly alter the physical properties of the wild-type signal peptide. In the presence of lipid vesicles which mimic the composition of the Escherichia coli inner membrane, the peptides adopt alpha-helical structure, and the tryptophan fluorescence emission maximum is shifted to shorter wavelength, indicating that the peptides insert into the acyl chain region of the lipid bilayer. Fluorescence quenching by soluble, aqueous-phase (I-), and membrane-resident (nitroxide-labeled lipids) quenchers was used to locate the tryptophans in each peptide within the bilayer. The C-terminus was interfacial while the central region of the signal sequence was deeply buried within the acyl chain region of the bilayer. The tryptophan at position 5 was buried but less deeply than the tryptophan at position 18. This topology is consistent with either a looped or a transmembrane orientation of signal peptide. However, either structure must accommodate the high helical content of the peptides in vesicles. These results indicate that the LamB signal sequence spontaneously inserts into the acyl chain region of lipid membranes in the absence of any of the proteins involved in protein secretion.     

Surface binding of alamethicin stabilizes its helical structure: molecular dynamics simulations.

Alamethicin is an amphipathic alpha-helical peptide that forms ion channels. An early event in channel formation is believed to be the binding of alamethicin to the surface of a lipid bilayer. Molecular dynamics simulations are used to compare the structural and dynamic properties of alamethicin in water and alamethicin bound to the surface of a phosphatidylcholine bilayer. The bilayer surface simulation corresponded to a loosely bound alamethicin molecule that interacted with lipid headgroups but did not penetrate the hydrophobic core of the bilayer. Both simulations started with the peptide molecule in an alpha-helical conformation and lasted 2 ns. In water, the helix started to unfold after approximately 300 ps and by the end of the simulation only the N-terminal region of the peptide remained alpha-helical and the molecule had collapsed into a more compact form. At the surface of the bilayer, loss of helicity was restricted to the C-terminal third of the molecule and the rod-shaped structure of the peptide was retained. In the surface simulation about 10% of the peptide/water H-bonds were replaced by peptide/lipid H-bonds. These simulations suggest that some degree of stabilization of an amphipathic alpha-helix occurs at a bilayer surface even without interactions between hydrophobic side chains and the acyl chain core of the bilayer.     

X-ray diffraction study of lipid bilayer membranes interacting with amphiphilic helical peptides: diphytanoyl phosphatidylcholine with alamethicin at low concentrations.

A variety of amphiphilic helical peptides have been shown to exhibit a transition from adsorbing parallel to a membrane surface at low concentrations to inserting perpendicularly into the membrane at high concentrations. Furthermore, this transition has been correlated to the peptides' cytolytic activities. X-ray lamellar diffraction of diphytanoyl phosphatidylcholine-alamethicin mixtures revealed the changes of the bilayer structure with alamethicin concentration. In particular, the bilayer thickness decreases with increasing peptide concentration in proportion to the peptide-lipid molar ratio from as low as 1:150 to 1:47; the latter is near the threshold of the critical concentration for insertion. From the decreases of the bilayer thickness, one can calculate the cross sectional expansions of the lipid chains. For all of the peptide concentrations studied, the area expansion of the chain region for each adsorbed peptide is a constant 280 +/- 20 A2, which is approximately the cross sectional area of an adsorbed alamethicin. This implies that the peptide is adsorbed at the interface of the hydrocarbon region, separating the lipid headgroups laterally. Interestingly, the chain disorder caused by a peptide adsorption tends to spread over a large area, as much as 100 A in diameter. The theoretical basis of the long range nature of bilayer deformation is discussed.     

1-Alkanols and membranes: A story of attraction

Although 1-alkanols have long been known to act as penetration enhancers and anesthetics, the mode of operation is not yet understood. In this study, long-time molecular dynamics simulations have been performed to investigate the effect of 1-alkanols of various carbon chain lengths onto the structure and dynamics of dimyristoylphosphatidylcholine bilayers. The simulations were complemented by microcalorimetry, continuous bleaching and film balance experiments. In the simulations, all investigated 1-alkanols assembled inside the lipid bilayer within tens of nanoseconds. Their hydroxyl groups bound preferentially to the lipid carbonyl group and the hydrocarbon chains stretched into the hydrophobic core of the bilayer. Both molecular dynamics simulations and experiments showed that all 1-alkanols drastically affected the bilayer properties. Insertion of long-chain 1-alkanols decreased the area per lipid while increasing the thickness of the bilayer and the order of the lipids. The bilayer elasticity was reduced and the diffusive motion of the lipids within the bilayer plane was suppressed. On the other hand, integration of ethanol into the bilayer enlarged the area per lipid. The bilayer became softer and lipid diffusion was enhanced.     

Lipid and Peptide Dynamics in Membranes upon Insertion of n-alkyl-β-D-Glucopyranosides

The effect of nonionic detergents of the n-alkyl-β-D-glucopyranoside class on the ordering of lipid bilayers and the dynamics of membrane-embedded peptides were investigated with ²H- and ³¹P-NMR. 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was selectively deuterated at methylene segments C-2, C-7, and C-16 of the two fatty acyl chains. Two trans-membrane helices, WALP-19 and glycophorin A_71-98, were synthesized with Ala-d₃ in the central region of the α-helix. n-Alkyl-β-D-glucopyranosides with alkyl chains with 6, 7, 8, and 10 carbon atoms were added at increasing concentrations to the lipid membrane. The bilayer structure is retained up to a detergent/lipid molar ratio of 1:1. The insertion of the detergents leads to a selective disordering of the lipids. The headgroup region remains largely unaffected; the fatty acyl chain segments parallel to the detergent alkyl chain are only modestly disordered (10-20%), whereas lipid segments beyond the methyl terminus of the detergent show a decrease of up to 50%. The change in the bilayer order profile corresponds to an increase in bilayer entropy. Insertion of detergents into the lipid bilayers is completely entropy-driven. The entropy change accompanying lipid disorder is equivalent in magnitude to the hydrophobic effect. Ala-d₃ deuterated WALP-19 and GlycA_71-97 were incorporated into bilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine at a peptide/lipid molar ratio of 1:100 and measured above the 1,2-dimyristoyl-sn-glycero-3-phosphocholine gel/liquid-crystal phase transition. Well-resolved ²H-NMR quadrupole splittings were observed for the two trans-membrane helices, revealing a rapid rotation of the CD₃ methyl rotor superimposed on an additional rotation of the whole peptide around the bilayer normal. The presence of detergent fluidizes the membrane and produces magnetic alignment of bilayer domains but does not produce essential changes in the peptide conformation or dynamics.     

Molecular dynamics study of the lauryl alcohol-laurate model bilayer

Molecular dynamics (MD) calculation of the fluid phase lauryl alcohol-laurate bilayer has been executed based on Berendsen's surface-constrained model. Structure and dynamics of the bilayer have been investigated by analyzing the trajectories of the chain configurations. Newly defined correlation functions as well as the conventional ones showed that the tilt and bend of the chain play an important role in the bilayer structure, including behavior of the order parameter. Interpenetration of the layers as well as formation of collectively ordered small domains was also found. The calculated lateral diffusion coefficient was in satisfactory agreement with the experimental one. Successive jumps of the head group, rather than the hydrodynamic continuous motion, were observed. Between the jumps, the molecule librated in a local site. Time-dependent autocorrelation functions showed evidence of several different modes of the chain motion, whose time constant ranged from a few tenths of picoseconds to several tens of picoseconds.     

Membrane association and selectivity of the antimicrobial peptide NK‐2: a molecular dynamics simulation study

In an effort to better understand the initial mechanism of selectivity and membrane association of the synthetic antimicrobial peptide NK‐2, we have applied molecular dynamics simulation techniques to elucidate the interaction of the peptide with the membrane interfaces. A homogeneous dipalmitoylphosphatidylglycerol (DPPG) and a homogeneous dipalmitoylphosphatidylethanolamine (DPPE) bilayers were taken as model systems for the cytoplasmic bacterial and human erythrocyte membranes, respectively. The results of our simulations on DPPG and DPPE model membranes in the gel phase show that the binding of the peptide, which is considerably stronger for the negatively charged DPPG lipid bilayer than for the zwitterionic DPPE, is mostly governed by electrostatic interactions between negatively charged residues in the membrane and positively charged residues in the peptide. In addition, a characteristic distribution of positively charged residues along the helix facilitates a peptide orientation parallel to the membrane interface. Once the peptides reside close to the membrane surface of DPPG with the more hydrophobic side chains embedded into the membrane interface, the peptide initially disturbs the respective bilayer integrity by a decrease of the order parameter of lipid acyl chain close to the head group region, and by a slightly decrease in bilayer thickness. We found that the peptide retains a high content of helical structure on the zwitterionic membrane‐water interface, while the loss of α‐helicity is observed within a peptide adsorbed onto negatively charged lipid membranes. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.