Water-phospholipid interactions at the lipid bilayer/water interfaces are of essential importance for the dynamics, stability and function of biological membrane, and are also strongly associated with numerous biological processes at the interfaces of lipid bilayers. Various force fields, such as the united-atom Berger force field, its two improved versions by Kukol and by Poger, and the all-atom Slipid force field developed recently, can be applied to simulating the structures of lipid bilayer, with their structural predictions in good agreement with experimental data. In this work, we show that despite the similarity in structural predictions of lipid bilayers, there are observable differences in formation of hydrogen bonds and the interaction energy profiles between water and phospholipid groups at the lipid bilayer/water interfaces, when four force fields for dipalmitoylphosphatidylcholine (DPPC) phospholipids are employed in molecular dynamics simulations. In particular, the Slipid force field yields more hydrogen bonds between water and phospholipids and more symmetrical interaction energy distributions for the two carboxylic groups on their respective acyl tails, compared to the Berger and its two improved force fields. These differences are mainly attributed to the different interfacial water distributions and ability to form hydrogen bonds between interfacial water and oxygen atoms of the DPPC lipids using different force fields. These results would be helpful in understanding the behaviors of water as well as its interaction with phospholipids at the lipid bilayer/water interfaces, and provide a guide for making the appropriate choice on the force field in simulations of lipid bilayers.
We report the effect of lipid head-group dipole orientation on phase behaviour of phospholipid assembly. The work explains molecular-scale mechanism of ion-lipid, anesthetic-lipid interactions where reorientation of dipoles play important role in membrane potential modification. Molecular Dynamics simulations are performed to analyse structure-property relationship and dynamical behaviour of lipid biomembranes considering coarse-grained model interactions.
Combining extensive molecular dynamics simulations of lipid bilayer systems of varying chemical composition with single-trajectory analyses we systematically elucidate the stochastic nature of the lipid motion. We observe subdiffusion over more than four orders of magnitude in time, clearly stretching into the sub-microsecond domain. The lipid motion delicately depends on the lipid chemistry, the lipid phase, and especially on the presence of cholesterol. We demonstrate that fractional Langevin equation motion universally describes the lipid motion in all phases including the gel phase, and in…
Cholesterol (CHOL) drives lipid segregation and is thus a key player for the formation of lipid rafts and followingly for the ability of a cell to, e.g., enable selective agglomeration of proteins. The lipid segregation is driven by cholesterol's affinity for saturated lipids, which stands directly in relation to the ability of cholesterol to order the individual phospholipid (PL) acyl chains. In this work, Molecular Dynamics simulations of DPPC (Dipalmitoylphosphatidylcholine, saturated lipid) and DLiPC (Dilineoylphosphatidylcholine, unsaturated lipid) mixtures with cholesterol are used to el…
Acetaminophen (APAP) or Paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used DOPC, a commonly found phospholipid in mammalian cell membranes to synthesize large unilamellar vesicles to investigate how the incorpora…
We studied the adsorption of a charged protein onto an oppositely charged membrane, composed of mobile phospholipids of differing valence, using a statistical-thermodynamical approach. A two-block model was employed, one block corresponding to the protein-affected region on the membrane, referred to as the adsorption domain, and the other to the unaffected remainder of the membrane. We calculated the protein-induced lipid rearrangement in the adsorption domain as arising from the interplay between the electrostatic interactions in the system and the mixing entropy of the lipids. Equating the e…
Coarse-grained model for saturated (DCPC, DLPC, DMPC, DPPC, DSPC) and unsaturated (POPC, DOPC) phospholipids is introduced within the Single Chain Mean Field theory. A single set of parameters adjusted for DMPC bilayers gives an adequate description of equilibrium and mechanical properties of a range of saturated lipid molecules that differ only in length of their hydrophobic tails and unsaturated (POPC, DOPC) phospholipids which have double bonds in the tails. A double bond is modeled with a fixed angle of 120 degrees, while the rest of the parameters are kept the same as saturated lipids. Th…
We study the effect of cholesterol on the structure of dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayers. Using extensive molecular dynamics computer simulations at atomistic resolution we observe and quantify several structural changes upon increasing cholesterol content that are collectively known as the condensing effect: a thickening of the bilayer, an increase in lipid tail order, and a decrease in lateral area. We also observe a change in leaflet interdigitation and a lack thereof in the distributions of DPPC head group orientations. These results, obtained over a wide range of…
Lipid monolayers have been shown to represent a powerful tool in studying mechanical and thermodynamic properties of lipid membranes as well as their interaction with proteins. Using Einstein's theory of fluctuations we here demonstrate, that an experimentally derived linear relationship both between transition entropy S and area A as well as between transition entropy and charge q implies a linear relationships between compressibility κ_T, heat capacity c_π, thermal expansion coefficient α_T and electric capacity CT. We demonstrate that these couplings have strong predictive power as they all…
The equilibrium distance between two lipid bilayers stable in bulk water and in proximity of a substrate was investigated. Samples consisted of a homogeneous lipid bilayer, floating near an identical bilayer deposited on the hydrophilic surface of a silicon single crystal. Lipids were saturated di-acyl phosphocholines, with the number of carbon atoms per chain, n, varying from 16 to 20. The average and r.m.s. positions of the floating bilayer were determined by means of neutron specular reflectivity. Samples were prepared at room temperature (i.e. with the lipids in the gel phase) and measurem…
Basic understanding of biological membranes is of paramount importance as these membranes comprise the very building blocks of life itself. Cells depend in their function on a range of properties of the membrane, which are important for the stability and function of the cell, information and nutrient transport, waste disposal and finally the admission of drugs into the cell and also the deflection of bacteria and viruses. We have investigated the influence of ibuprofen on the structure and dynamics of L-alpha-phosphatidylcholine (SoyPC) membranes by means of grazing incidence small-angle neutr…
The dependence of the structure of a phospholipid layer (DSPC and SOPC) adsorbed on a hydrosol substrate on the concentration of NaOH in a solution of 5-nm silica particles has been studied by X-ray reflectrometry with the use of synchrotron radiation. Profiles of the electron density (polarizability) have been reconstructed from the experimental data within a model-independent approach. According to these profiles, the thickness of the lipid film can vary from a monolayer (~ 35 Angstrom) to several bilayers (~ 450 Angstrom). At the volume concentration of NaOH of ~ 0.5 mol/L, the film on the …
Ice formation in model biological membranes is studied by SAXS and WAXS in the presence of cryoprotectors: dimethyl sulfoxide and glycerol. Three types of phospholipid membranes: DPPC, DMPC, DSPC are chosen for the investigation as well-studied model biological membranes. A special cryostat is used for sample cooling from 14.1C to -55.4C. The ice formation is only detected by WAXS in binary phospholipid/water and ternary phospholipid/cryoprotector/water systems in the condition of excess solvent. Ice formation in a binary phospholipid/water system creates an abrupt decrease of the membrane rep…
I introduce an alternative interpretation for the short-time anomalous diffusion observed by Gupta et al. using neutron spin echo. The interpretation involves the Brochard-Lennon "red blood cell" mode to describe membrane thickness fluctuations, and yields an anomalous diffusion exponent 1/3 that is consistent with the experimental results.
Duncan Dowson, whom this issue commemorates, was a world leader in the field of biotribology, with prolific contributions both in fluid-based and boundary lubrication of biological tissues, in particular articular cartilage, a central issue in biotribology due to its importance for joint homeostasis. Here we explore further the issue of cartilage boundary lubrication, which has been attributed to phospholipid (PL)-exposing layers at the cartilage surface in part. A surface force balance (SFB) with unique sensitivity is used to investigate the normal and frictional interactions of the boundary …
The structure of the transient layer at the interface between air and the aqueous solution of silica nanoparticles with the size distribution of particles that has been determined from small-angle scattering has been studied by the X-ray reflectometry method. The reconstructed depth profile of the polarizability of the substance indicates the presence of a structure consisting of several layers of nanoparticles with the thickness that is more than twice as large as the thickness of the previously described structure. The adsorption of 1,2-distearoyl-sn-glycero-3-phosphocholine molecules at the…
Water hydrating phospholipid membranes determine their stability and function, as well as their interaction with other molecules. In this article we study, using all-atom molecular dynamics simulations, the rotational and translational dynamical properties of water molecules confined in stacked phospholipid membranes at different levels of hydration, from poorly hydrated to a completely hydrated membrane. We find that both the translational and the reorientation dynamics of water are dramatically slowed down as the hydration is reduced. Analyzing in details the structure and dynamics of the hy…
We present the derivation of a new model to describe neutron spin echo spectroscopy and quasi-elastic neutron scattering data on liposomes. We compare the new model with existing approaches and benchmark it with experimental data. The analysis indicates the importance of including all major contributions into modeling of the intermediate scattering function. Simultaneous analysis of the experimental data on lipids with full contrast and tail contrast matched samples, reveals highly confined lipid tail motion. A comparison of their dynamics demonstrates the statistical independ-ence of tail-mot…
Nanoparticles with hydrophobic capping ligands and amphiphilic phospholipids are both found to self-assemble into monolayer films when deposited on the air water interface. By separately measuring the anisotropic stress response of these films under uniaxial compression, we obtain both the 2D compressive and shear moduli of a range of different thin nanoparticle and phospholipid films. The compressive moduli of both nanoparticle and lipid films in the solid phase are on the same order of magnitude, whereas the shear moduli of the lipid films are found to be significantly lower. Additionally th…
In this paper the problem of surface charge of the lipid membrane immersed in the physiological solution is considered. It is shown that both side of the bilayer phospholipid membrane surface are negatively charged. A self-consistent model of the potential in solution is developed, and a stationary charge density on the membrane surface is found. It is shown that the ions of the surface charge are in a relatively deep (as compared to kBT) potential wells, which are localized near the dipole heads of phospholipid membrane. It makes impossible for ions to slip along the membrane surface. Simple …
Cholesterol (CHOL) is one of the most important components of plasma membranes of higher cells and one of the main factors for the formation of (nano)domains. In this work, molecular dynamics simulations of mixtures of CHOL with DPPC (saturated lipid) and DLiPC (unsaturated lipid) as standard phospholipids (PLs) are presented in a wide range of CHOL concentrations. The key idea is to systematically extract all structural and enthalpic properties relevant to the formulation of a lattice model of these systems and express them in dependence of the acyl chain order parameters. Detailed interpreta…
We report results concerning the destabilisation of supported phospholipid bilayers in a well-defined geometry. When heating up supported phospholipid membranes deposited on highly hydrophilic glass slides from room temperature (i.e. with lipids in the gel phase), unbinding was observed around the main gel to fluid transition temperature of the lipids. It lead to the formation of relatively monodisperse vesicles, of which most remained tethered to the supported bilayer. We interpret these observations in terms of a sharp decrease of the bending rigidity modulus $κ$ in the transition region, co…
An interfacial regularized Stokeslet scheme is presented to predict the motion of solid bodies (e.g. proteins or gel-phase domains) embedded within flowing lipid bilayer membranes. The approach provides a numerical route to calculate velocities and angular velocities in complex flow fields that are not amenable to simple Faxén-like approximations. Additionally, when applied to shearing motions, the calculations yield predictions for the effective surface viscosity of dilute rigid body-laden membranes. In the case of cylindrical proteins, effective viscosity calculations are compared to two pri…
By reverting to spectroscopy, changes in the biological environment of a fluorescent probe can be monitored and the presence of various phases of the surrounding lipid bilayer membranes can be detected. This study highlights the important differences in orientation and location and therefore in efficiency between the probes when they are used in fluorescence microscopy to screen various lipid bilayer membrane phases. Dependent on the lipid composition, the angle between the transition state dipole moments of both probes and the normal to the membrane are found to deviate clearly from 90°. It i…
The molecular structure of a multilayer of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) adsorbed on the surface of the hydrosol of silica nanoparticles has been studied by the synchrotron radiation scattering method. According to the reflectometry data, the multilayer is formed by planar phospholipid bilayers with a thickness of 69 +/- 1 Angstrom and its total thickness is about 400 Angstrom. Grazing-incidence diffraction indicates that the bilayers are in the crystal state with an area of 41.6 +/- 0.7 Angstrom^2 per molecule.
Specific lipid environments are necessary for the establishment of protein signalling platforms in membranes, yet their origin has been highly debated. We present a continuum, exactly solvable model of protein induced local demixing of lipid membranes. The coupling between a local composition and a local thickness of the membrane induces lipid domains around inclusions with hydrophobic mismatch, even for temperatures above the miscibility critical point of the membrane. The model qualitatively explains the experimentally observed formation of lipid domains induced by anchoring of reconstituted…
Cells use homeostatic mechanisms to maintain an optimal composition of distinct types of phospholipids in cellular membranes. The hydrophilic dipolar layer at the membrane interface, composed of phospholipid headgroups, regulates the interactions between cell membranes and incoming molecules, nanoparticles, and viruses. On the other hand, the membrane hydrophobic core determines membrane thickness and forms an environment for membrane-bound molecules such as transmembrane proteins. A fundamental open question is to what extent the motions of these regions are coupled and, consequently, how str…
We present the first inelastic neutron scattering study of the short wavelength dynamics in a phospholipid bilayer. We show that inelastic neutron scattering using a triple-axis spectrometer at the high flux reactor of the ILL yields the necessary resolution and signal to determine the dynamics of model membranes. The results can quantitatively be compared to recent Molecular Dynamics simulations. Reflectivity, in-plane correlations and the corresponding dynamics can be measured simultaneously to gain a maximum amount of information. With this method, dispersion relations can be measured with …
We use coarse grained molecular dynamics simulations to investigate diffusion properties of sheared lipid membranes with embedded transmembrane proteins. In membranes without proteins, we find normal in-plane diffusion of lipids in all flow conditions. Protein embedded membranes behave quite differently: by imposing a simple shear flow and sliding the monolayers of the membrane over each other, the motion of protein clusters becomes strongly superdiffusive in the shear direction. In such a circumstance, subdiffusion regime is predominant perpendicular to the flow. We show that superdiffusion i…
Over recent decades, lipid membranes have become standard models for examining the biophysics and biochemistry of cell membranes. Interrogation of lipid domains within biomembranes is generally done with fluorescence microscopy via exogenous chemical probes. However, most fluorophores have limited partitioning tunability, with the majority segregating in the least biologically relevant domains (i.e., low-density liquid domains). Therefore, a molecular-level picture of the majority of non-labeled lipids forming the membrane is still elusive. Here, we present simple, label-free imaging of domain…
Lipid membranes are abundant in living organisms, where they constitute a surrounding shell for cells and their organelles. There are many circumstances in which the deformations of lipid membranes are involved in living cells: fusion and fission, membrane-mediated interaction between membrane inclusions, lipid-protein interaction, formation of pores, etc. In all of these cases, elastic parameters of lipid membranes are important for the description of membrane deformations, as these parameters determine energy barriers and characteristic times of membrane-involved phenomena. Since the develop…
Biological membranes are essential for the cell life and hydration water provides the driving force for their assembly and stability. Here we study the structural properties of water in a phospholipid membrane. We characterize local structures inspecting the intermediate range order (IRO) adopting a sensitive local order metric, recently proposed by Martelli et al., which measures and grades the degree of overlap of local environments with structures of perfect ice. Close to the membrane, water acquires high IRO and changes its dynamical properties, e.g., slowing down its translational and rot…
The propagation of sound waves on lipid monolayers supported on water has been studied during the melting transition. Since changes in volume, area, and compressibility in lipid membranes have biological relevance, the observed sound propagation is of paramount importance. However, it is unknown what would occur on a lipid bilayer, which is a more approximate model of a cell membrane. With the aim to answer this relevant question, we built an experimental setup to assemble long artificial lipid membranes. We found that if these membranes are heated in order to force local melting, a thermo-mec…
A novel two-leaflet description of lipid membranes is proposed. Within its framework, phase separation phenomena in multicomponent biological membranes are analyzed. As we show, interactions between the leaflets tend to suppress macroscopic phase segregation (i.e., complete demixing of lipids) in such systems. Instead, microphase separation characterized by formation of equilibrium nanoscale domains can take place. The phase diagram is constructed and numerical simulations revealing nanostructures of different morphology are performed.
Simulating Curved Lipid Membranes Using Anchored Frozen Patches
Department of Materials Science and Engineering, Grainger College of Engineering, University of Illinois Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校格雷恩工程学院材料科学与工程系）
The Stratum Corneum (SC), the outermost layer of skin, comprises rigid corneocytes (keratin filled dead cells) in a specialized lipid matrix. The continuous lipid matrix provides the main barrier against uncontrolled water loss and invasion of external pathogens. Unlike all other biological lipid membranes (like intracellular organelles and plasma membranes), molecules in SC lipid matrix show small hydrophilic group and large variability in the length of the alkyl tails and in the numbers and positions of groups that are capable of forming hydrogen bonds. Molecular simulations provide a route …
We develop a model of interacting zwitterionic membranes with rotating surface dipoles immersed in a monovalent salt, and implement it in a field theoretic formalism. In the mean-field regime of monovalent salt, the electrostatic forces between the membranes are characterized by a non-uniform trend: at large membrane separations, the interfacial dipoles on the opposing sides behave as like-charge cations and give rise to repulsive membrane interactions; at short membrane separations, the anionic field induced by the dipolar phosphate groups sets the behavior in the intermembrane region. The at…
Lipid rafts are heterogeneous dynamic lipid domains of the cell membranes that are involved in several biological processes, like protein and lipids specific transport and signaling. Our understanding of lipid raft formation is still limited, due to the transient and elusive nature of these domains {\it in vivo}, in contrast to the stable phase-separated domains observed in artificial membranes. Inspired by experimental findings highlighting the relevance of transmembrane proteins for lipid rafts, we investigate lipid domain nucleation by coarse-grained molecular dynamics and Ising model simul…
By performing molecular dynamics simulations with up to 132 million coarse-grained particles in half-micron sized boxes, we show that hydrodynamics quantitatively explains the finite-size effects on diffusion of lipids, proteins, and carbon nanotubes in membranes. The resulting Oseen correction allows us to extract infinite-system diffusion coefficients and membrane surface viscosities from membrane simulations despite the logarithmic divergence of apparent diffusivities with increasing box width. The hydrodynamic theory of diffusion applies also to membranes with asymmetric leaflets and embed…
The external electric field deforms flaccid phospholipid vesicles into spheroidal bodies, with the rotational axis aligned with its direction. Deformation is frequency dependent: in the low frequency range (~ 1 kHz), the deformation is typically prolate, while increasing the frequency to the 10 kHz range changes the deformation to oblate. We attempt to explain this behaviour with a theoretical model, based on the minimization of the total free energy of the vesicle. The energy terms taken into account include the membrane bending energy and the energy of the electric field. The latter is calcu…
Metastable states in first-order phase-transitions have been traditionally described by classical nucleation theory (CNT). However, recently an increasing number of systems displaying such a transition have not been successfully modelled by CNT. The delayed crystallization of phospholipids upon super-cooling is an interesting case, since the extended timescales allow access into the dynamics. Herein, we demonstrate the controllable behavior of the long-lived metastable liquid-crystalline phase of dilauroyl-phosphatidylethanolamine (DLPE), arranged in multi-lamellar vesicles, and the ensuing co…
We propose a model describing the phase behavior of two-component membranes consisting of binary mixtures of electrically charged and neutral lipids. We take into account the structural phase transition (main-transition) of the hydrocarbon chains, and investigate the interplay between this phase transition and the lateral phase separation. The presence of charged lipids significantly affects the phase behavior of the multi-component membrane. Due to the conservation of lipid molecular volume, the main-transition temperature of charged lipids is lower than that of neutral ones. Furthermore, as …
We apply recently developed phenomenological theory of polar liquids to calculate the repulsive pressure between two hydrophilic membranes at nm-distances. We find that the repulsion does show up in the model and the solution to the problem fits the published experimental data well both qualitatively and quantitatively. Moreover, we find that the repulsion is practically independent on temperature, and thus put some extra weight in favour of the so called hydration over entropic hypothesis for the membranes interactions explanation. The calculation is a good proof of concept example a continuo…
A new model for the interaction of an electric pulse with a lipid membrane is proposed. Using this model we show that when a DC electric pulse is applied to an insulating lipid membrane separating fluids with different conductivities, the capacitive charging current through the membrane drives electrohydrodynamic flow that destabilizes the membrane. The instability is transient and decays as the membrane charges. The bulk conductivity mismatch plays an essential role in this instability because it results in a different rate of charge accumulation on the membrane's physical surfaces. Shearing …
By means of lattice-based Monte Carlo simulations, we address properties of two-component lipid membranes on the experimentally relevant spatial scales of order of a micrometer and time intervals of order of a second, using DMPC/DSPC lipid mixtures as a model system. Our large-scale simulations allowed us to obtain important results previously not reported in simulation studies of lipid membranes. We find that, within a certain range of lipid compositions, the phase transition from the fluid phase to the fluid-gel phase coexistence proceeds via near-critical fluctuations, while for other lipid…
We employ 100 ns molecular dynamics simulations to study the influence of cholesterol on structural and dynamic properties of dipalmitoylphosphatidylcholine (DPPC) bilayers in the fluid phase. The effects of the cholesterol content on the bilayer structure are considered by varying the cholesterol concentration between 0 and 50%. We concentrate on the free area in the membrane and investigate quantities that are likely to be affected by changes in the free area and free volume properties. It is found that cholesterol has a strong impact on the free area properties of the bilayer. The changes i…
We study the indentation of a free-standing lipid membrane suspended over a nanopore on a hydrophobic substrate by means of molecular dynamics simulations. We find that in the course of indentation, the membrane bends at the point of contact, and the fringes of the membrane glide downward intermittently along the pore edges and stop gliding when the fringes reach the edge bottoms. The bending continues afterwards, and the large strain eventually induces a phase transition in the membrane, transformed from a bilayered structure to an interdigitated structure. The membrane is finally ruptured wh…
Bilayer lipid membranes [BLMs] are an essential component of all biological systems, forming a functional barrier for cells and organelles from the surrounding environment. The lipid molecules that form membranes contain both permanent and induced dipoles, and an electric field can induce the formation of pores when the transverse field is sufficiently strong (electroporation). Here, a phenomenological free energy is constructed to model the response of a BLM to a transverse static electric field. The model contains a continuum description of the membrane dipoles and a coupling between the hea…
We investigate how an externally imposed curvature influences lipid segregation on two-phase-coexistent membranes. We show that the bending-modulus contrast of the two phases and the curvature act together to yield a reduced effective line tension. On largely curved membranes, a state of multiple domains (or rafts) forms due to a mechanism analogous to that causing magnetic-vortex formation in type-II superconductors. We determine the criterion for such multi-domain state to occur; we then calculate respectively the size of the domains formed on cylindrically and spherically curved membranes.
We study the deformation of a lipid membrane in response to a local pH modification. Experimentally, a basic solution is microinjected close to a giant unilamellar vesicle. A local deformation appears in the zone of the membrane that is closest to the micropipette, and relaxes when the injection is stopped. A theoretical description of this phenomenon is provided. It takes fully into account the spatiotemporal evolution of the concentration of hydroxide ions during and after the microinjection, as well as the linear dynamics of the membrane. This description applies to a local injection of any…
We formulate a theory of electrostatic interactions in lipid bilayer membranes where both monolayer leaflets contain dissociable moieties that are subject to charge regulation. We specifically investigate the coupling between membrane curvature and charge regulation of a lipid bilayer vesicle using both the linear Debye-Hückel (DH) and the non-linear Poisson-Boltzmann (PB) theory. We find that charge regulation of an otherwise symmetric bilayer membrane can induce charge symmetry breaking, non-linear flexoelectricity and anomalous curvature dependence of free energy. The pH effects investigate…
The theory of irreversible thermodynamics for arbitrarily curved lipid membranes is presented here. The coupling between elastic bending and irreversible processes such as intra-membrane lipid flow, intra-membrane phase transitions, and protein binding and diffusion is studied. The forms of the entropy production for the irreversible processes are obtained, and the corresponding thermodynamic forces and fluxes are identified. Employing the linear irreversible thermodynamic framework, the governing equations of motion along with appropriate boundary conditions are provided.
