We investigate the possible influence of poly unsaturated fatty acids (PUFAs) in the lipid bilayer of cell membranes on the conduction properties of the selectivity filter of voltage gated ion channels. Any change of this conductivity can have major consequences on electrical signalling in brain and other cells. At the microscopic level a change in the concentration of PUFAs can cause a change in the pressure distribution within the lipid bilayer, and this in turn can lead to a change in the length of the selectivity filter. In order to estimate the consequences this might entail for the ion channel's conductivity we performed high resolution molecular dynamics (MD) simulations of the passage of K+ ions and H2O molecules through the selectivity filter of the KcsA potassium ion channel. Our results show that a change in length of the selectivity filter of as little as 4%, independent of whether the filter is made longer or shorter, will reduce the K+ ion current by around 50%. And further squeezing or stretching by about 10% can effectively stop the current. For instructive purposes and to facilitate further interpretation of the results, we give details of the force models employed in the MD simulations. We finally discuss the present results in the context of possible effects of membrane lipid compositions on Kv ion permeation.
In an effort to understand ``rafts'' in biological membranes, we propose phenomenological models for saturated and unsaturated lipid mixtures, and lipid-cholesterol mixtures. We consider simple couplings between the local composition and internal membrane structure, and their influence on transitions between liquid and ``gel'' membrane phases. Assuming that the gel transition temperature of the saturated lipid is shifted by the presence of the unsaturated lipid, and that cholesterol acts as an external field on the chain melting transition, a variety of phase diagrams are obtained. The phase d…
We use a long, all-atom molecular dynamics (MD) simulation combined with theoretical modeling to investigate the dynamics of selected lipid atoms and lipid molecules in a hydrated diyristoyl-phosphatidylcholine (DMPC) lipid bilayer. From the analysis of a 0.1 $μ$s MD trajectory we find that the time evolution of the mean square displacement, [δ{r}(t)]^2, of lipid atoms and molecules exhibits three well separated dynamical regions: (i) ballistic, with [δ{r}(t)]^2 ~ t^2 for t < 10 fs; (ii) subdiffusive, with [δ{r}(t)]^2 ~ t^β with β<1, for 10 ps < t < 10 ns; and (iii) Fickian diffusion, with [δ{…
Random lateral translocation of lipids and proteins is a universal process on membrane surfaces. Local aggregation or organization of lipids and proteins can be induced when this lateral random diffusion is mediated by the electrostatic interactions and membrane curvature. Though the lateral diffusion rates of lipids on membrane of various compositions are measured and the electrostatic free energies of predetermined protein-membrane-lipid systems can be computed, the process of the aggregation and the evolution to the electrostatically favorable states remain undetermined. Here we propose an …
Engineering the synthetic nanopores through lipid bilayer membrane to access the interior of a cell is a long persisting challenge in biotechnology. Here, we demonstrate the stability and dynamics of a tile-based 6-helix DNA nanotube (DNT) embedded in POPC lipid bilayer using the analysis of 0.2 microsecond long equilibrium MD simulation trajectories. We observe that the head groups of the lipid molecules close to the lumen cooperatively tilt towards the hydrophilic sugar-phosphate backbone of DNA and form a toroidal structure around the patch of DNT protruding in the membrane. Further, we exp…
We use coarse-grained Monte Carlo simulations to study the elastic properties of charged membranes in solutions of monovalent and pentavalent counterions. The simulation results of the two cases reveal trends opposite to each other. The bending rigidity and projected area increase with the membrane charge density for monovalent counterions, while they decrease for the pentavalent ions. These observations can be related to the counterion screening of the lipid charges. While the monovalent counterions only weakly screen the Coulomb interactions, which implies a repulsive Coulomb system, the mul…
Biomembranes, which are mainly composed of neutral and charged lipids, exhibit a large variety of functional structures and dynamics. Here, we report a coarse-grained molecular dynamics (MD) simulation of the phase separation and morphological dynamics in charged lipid bilayer vesicles. The screened long-range electrostatic repulsion among charged head groups delays or inhibits the lateral phase separation in charged vesicles compared with neutral vesicles, suggesting the transition of the phase-separation mechanism from spinodal decomposition to nucleation or homogeneous dispersion. Moreover,…
Artificial bilayer lipid membranes (BLMs), along with patch-clamped membranes, are frequently used for functional analyses of membrane proteins. In both methods, the electric properties of membranes are characterized by only one parameter, namely, transmembrane potential. Here the construction of a novel BLM system was reported, in which membrane voltages can be controlled in a lateral direction in addition to conventional transmembrane direction. A microaperture was fabricated in a Teflon film and Ti electrodes were evaporated around the aperture. BLMs were reproducibly formed in the aperture…
This paper considers the effect of electrostatics on the stability of a charged membrane. We show that at low ionic strength and high surface charge density, repulsion between charges on the membrane renders it unstable to the formation of holes. A free straight edge is unstable to modulations with wavelength longer than the Debye screening length. Hence at low ionic strength, membranes will disintegrate into vesicles. We use these results to interpret stable holes in red blood cell ghosts (Steck et. al., Science 168:255(1970)).
Sound waves are excited on lipid monolayers using a set of planar electrodes aligned in parallel with the excitable medium. By measuring the frequency dependent change in the lateral pressure we are able to extract the sound velocity for the entire monolayer phase diagram. We demonstrate that this velocity can also be directly derived from the lipid monolayer compressibility and consequently displays a minimum in the phase transition regime. This minimum decreases from v0=170m/s for one component lipid monolayers down to vm=50m/s for lipid mixtures. No significant attenuation can be detected c…
To understand mechanism of cell-membrane compartmentalization, we studied coarse-grained model systems consisting of lipid and cholesterol molecules. Cholesterol plays crucial role in lateral phase segregation in the bilayered lipid membrane to form cholesterol rich liquid ordered domains, termed as `rafts'. In this NVT Molecular Dynamics simulation study, we have investigated the role of cholesterol in raft-like domain formation. The study reveals that the strength of cholesterol interaction is an important factor behind the phase segregation to form cholesterol rich domains, whereas, the rel…
We show that the activity of an ion channel is strictly related to the phase state of the lipid bilayer hosting the channel. By measuring unitary conductance, dwell times, and open probability of the K+ channel KcsA as a function of temperature in lipid bilayers composed of POPE and POPG in different relative proportions, we obtain that all those properties show a trend inversion when the bilayer is in the transition region between the liquid disordered and the solid ordered phase. These data suggest that the physical properties of the lipid bilayer influence ion channel activity likely via a …
We show that lateral fluidity in membranes containing quenched protein obstacles belongs to the universality class of the two-dimensional random-field Ising model. The main feature of this class is the absence of a phase transition: there is no critical point, and macroscopic domain formation does not occur. Instead, there is only one phase. This phase is highly heterogeneous, with a structure consisting of micro-domains. The presence of quenched protein obstacles thus provides a mechanism to stabilize lipid rafts in equilibrium. Crucial for two-dimensional random-field Ising universality is t…
Among other improvements, the Martini 3 coarse-grained force field provides a more accurate description of the solvation of protein pockets and channels through the consistent use of various bead types and sizes. Here, we show that the representation of Na$^+$ and Cl$^-$ ions as "tiny" (TQ5) beads limits the accessible time step to 25 fs. By contrast, with Martini 2, time steps of 30-40 fs were possible for lipid bilayer systems without proteins. This limitation is relevant for, e.g., phase separating lipid mixtures that require long equilibration times. We derive a quantitative kinetic model …
We discuss different mechanisms for curvature-induced domain formation in multicomponent lipid membranes and present a theoretical model that allows us to study the interplay between the domains. The model represents the membrane by two coupled monolayers, which each carry an additional order parameter field describing the local lipid composition. The spontaneous curvature of each monolayer is coupled to the local composition, moreover, the lipid compositions on opposing monolayers are coupled to each other. Using this model, we calculate the phase behavior of the bilayer in mean-field approxi…
In experiments on model membranes, a formation of large domains of different lipid composition is readily observed. However, no such phase separation is observed in the membranes of intact cells. Instead, a structure of small transient inhomogeneities called lipid rafts are expected in these systems. One of the numerous attempts to explain small domains refers to the coupling of the membrane to its surroundings, which leads to the immobilization of some of the membrane molecules. These immobilized molecules then act as static obstacles for the remaining mobile ones. We present detailed Molecul…
A coarse-grained molecular model, which consists of a spherical particle and an orientation vector, is proposed to simulate lipid membrane on a large length scale. The solvent is implicitly represented by an effective attractive interaction between particles. A bilayer structure is formed by orientation-dependent (tilt and bending) potentials. In this model, the membrane properties (bending rigidity, line tension of membrane edge, area compression modulus, lateral diffusion coefficient, and flip-flop rate) can be varied over broad ranges. The stability of the bilayer membrane is investigated v…
It is known that lipid membranes become permeable in their melting regime. In microscopic conductance measurements on black lipid membranes one finds that conduction takes place via quantized events closely resembling those reported for protein ion channels. Here, we present data of ion currents through black lipid membranes in the presence and absence of the anesthetics octanol and ethanol, and compare them to a statistical thermodynamics model using parameters that are obtained from experimental calorimetric data. The conductance steps in pure lipid membrane suggest aqueous pores with the si…
Hydrated interfaces are ubiquitous in biology and appear on all length scales from ions, individual molecules to membranes and cellular networks. In vivo, they comprise a high degree of self-organization and complex entanglement, which limits their experimental accessibility by smearing out the individual phenomenology. The Langmuir technique, however, allows the examination of defined interfaces, whose controllable thermodynamic state enables one to explore the proper state diagrams. Here we demonstrate that voltage and pressure pulses simultaneously propagate along monolayers comprised of ei…
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 …
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…
Ever since the raft model for biomembranes has been proposed, the traditional view of biomembranes based on the fluid-mosaic model has been altered. In the raft model, dynamical heterogeneities in multi-component lipid bilayers play an essential role. Focusing on the lateral phase separation of biomembranes and vesicles, we review some of the most relevant research conducted over the last decade. We mainly refer to those experimental works that are based on physical chemistry approach, and to theoretical explanations given in terms of soft matter physics. In the first part, we describe the pha…
Biomembranes are thin capacitors with the unique feature of displaying phase transitions in a physiologically relevant regime. We investigate the voltage and lateral pressure dependence of their capacitance close to their chain melting transition. Since the gel and the fluid membrane have different area and thickness, the capacitance of the two membrane phases is different. In the presence of external fields, charges exert forces that can influence the state of the membrane, thereby influencing the transition temperature. This phenomenon is called electrostriction. We show that this effect all…
Despite a vast clinical application of anesthetics, the molecular level of understanding of general anesthesia is far from our reach. Using atomistic molecular dynamics simulation, we study the effects of common anesthetics: ethanol, chloroform and methanol in the fully hydrated symmetric multicomponent lipid bilayer membrane comprising of an unsaturated palmitoyl-oleoyl-phosphatidyl-choline (POPC), a saturated palmitoyl-sphingomyelin (PSM) and cholesterol (Chol) which exhibits phase coexistence of liquid-ordered (lo) - liquid disordered (ld) phase domains. We find that the mechanical and phys…
According to the lipid raft hypothesis, biological lipid membranes are laterally heterogeneous and filled with nanoscale ordered "raft" domains, which are believed to play an important role for the organization of proteins in membranes. However, the mechanisms stabilizing such small rafts are not clear, and even their existence is sometimes questioned. Here we report the observation of raft-like structures in a coarse-grained molecular model for multicomponent lipid bilayers. On small scales, our membranes demix into a liquid ordered (lo) and a liquid disordered (ld) phase. On large scales, ph…
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…
Rafts, or functional domains, are transient nano- or mesoscopic structures in the plasma membrane and are thought to be essential for many cellular processes such as signal transduction, adhesion, trafficking and lipid/protein sorting. Observations of these membrane heterogeneities have proven challenging, as they are thought to be both small and short-lived. With a combination of coarse-grained molecular dynamics simulations and neutron diffraction using deuterium labeled cholesterol molecules we observe raft-like structures and determine the ordering of the cholesterol molecules in binary ch…
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…
Synthetic lipid membranes in the absence of proteins can display quantized conduction events for ions that are virtually indistinguishable from those of protein channel. By indistinguishable we mean that one cannot decide based on the current trace alone whether conductance events originate from a membrane, which does or does not contain channel proteins. Additional evidence is required to distinguish between the two cases, and it is not always certain that such evidence can be provided. The phenomenological similarities are striking and span a wide range of phenomena: The typical conductances…
Colloids and proteins alike can bind to lipid bilayers and move laterally in these two-dimensional fluids. Inspired by proteins that generate membrane curvature, sense the underlying membrane geometry, and migrate to high curvature sites, we explore the question: Can colloids, adhered to lipid bilayers, also sense and respond to membrane geometry? We report the curvature migration of Janus microparticles adhered to giant unilamellar vesicles elongated to present well defined curvature fields. However, unlike proteins, which migrate to minimize membrane bending energy, colloids migrate by an en…
Recent experiments have shown that when a near-hemispherical lipid vesicle attached to a solid surface is subjected to a simple shear flow it exhibits a pattern of membrane circulation much like a dipole vortex. This is in marked contrast to the toroidal circulation that would occur in the related problem of a drop of immiscible fluid attached to a surface and subjected to shear. This profound difference in flow patterns arises from the lateral incompressibility of the membrane, which restricts the observable flows to those in which the velocity field in the membrane is two-dimensionally diver…
Lipid bilayer membranes are flexible thin laterally fluid films consisting of two unimolecular layers of lipids. On spatial scales much larger than the bilayer thickness, the membrane elasticity is well determined by its shape and adequately described by the classical Helfrich Hamiltonian. However, various local membrane heterogeneities can result in a lipids tilt relative to the membrane surface normal. On the basis of the classical elasticity theory of 3D bodies, Hamm and Kozlov [Eur. Phys. J. E 3, 323 (2000)] derived the most general energy functional, taking into account the tilt and bendi…
The study of vesicles in suspension is important to understand the complicated dynamics exhibited by cells in vivo and in vitro. We developed a computer simulation based on the boundary-integral method to model the three dimensional gravity-driven sedimentation of charged vesicles towards a flat surface. The membrane mechanical behavior was modeled using the Helfrich Hamiltonian and near incompressibility of the membrane was enforced via a model which accounts for the thermal fluctuations of the membrane. The simulations were verified and compared to experimental data obtained using suspended …
We propose a model that accounts for budding behavior of domains in lipid bilayers, where each of the bilayer leaflets has a coupling between its local curvature and local lipid composition. The compositional asymmetry between the two monolayers leads to an overall spontaneous curvature. The membrane free-energy contains three contributions: bending energy, line tension, and a Landau free-energy for a lateral phase separation. Within a mean-field treatment, we obtain various phase diagrams which contain fully-budded, dimpled and flat states. In particular, for some range of membrane parameters…
Ion channels are membrane proteins responsible for an enormous range of biological functions. Ion selectivity and permeation are based on simple laws of physics and chemistry. Ion channels are therefore ideal candidates for physical investigation. A reduced model generates the selectivity of voltage-gated L-type calcium channel under a wide range of ionic conditions using only two parameters with unchanging values. The reasons behind the success of this reduced model are investigated. Monte Carlo simulations are performed investigating the role of flexibility of the side chains in the selectiv…
The statistical and dynamical properties of ions in the selectivity filter of the KcsA ion channel are considered on the basis of molecular dynamics (MD) simulations of the KcsA protein embedded in a lipid membrane surrounded by an ionic solution. A new approach to the derivation of a Brownian dynamics (BD) model of ion permeation through the filter is discussed, based on unbiased MD simulations. It is shown that depending on additional assumptions, ion's dynamics can be described either by under-damped Langevin equation with constant damping and white noise or by Langevin equation with a frac…
Sensory hair cells in auditory and vestibular organs rely on active mechanisms to achieve high sensitivity and frequency selectivity. Recent experimental studies have documented self-sustained oscillations in hair cells of lower vertebrates on two distinct levels. First, the hair bundle can undergo spontaneous mechanical oscillations. Second, somatic electric voltage oscillations across the baso-lateral membrane of the hair cell have been observed. We develop a biophysical model of the bullfrog's saccular hair cell consisting of two compartments, mechanical and electrical, to study how the mec…
