Lipid-protein interaction induced domains: Kinetics and conformational changes in multicomponent vesicles.

The spatio-temporal organization of proteins and the associated morphological changes in membranes are of importance in cell signaling. Several mechanisms that promote the aggregation of proteins at low cell surface concentrations have been investigated in the past. We show, using Monte Carlo simulations, that the affinity of proteins for specific lipids can hasten their aggregation kinetics. The lipid membrane is modeled as a dynamically triangulated surface with the proteins defined as in-plane fields at the vertices. We show that, even at low protein concentrations, strong lipid-protein interactions can result in large protein clusters indicating a route to lipid mediated signal amplification. At high protein concentrations, the domains form buds similar to that seen in lipid-lipid interaction induced phase separation. Protein interaction induced domain budding is suppressed when proteins act as anisotropic inclusions and exhibit nematic orientational order. The kinetics of protein clustering and resulting conformational changes are shown to be significantly different for the isotropic and anisotropic curvature inducing proteins.

Kosmotropic effect leads to LCST decrease in thermoresponsive polymer solutions.

We study the phenomena of decrease in lower critical solution temperature (LCST) with addition of kosmotropic (order-making) cosolvents in thermoresponsive polymer solutions. A combination of explicit solvent coarse-grained simulations and mean-field theory has been employed. The polymer-solvent LCST behavior in the theoretical models has been incorporated through the Kolomeisky-Widom solvophobic potential. Our results illustrate how the decrease in the LCST can be achieved by the reduction in the bulk solvent energy with the addition of cosolvent. It is shown that this effect of cosolvent is weaker with an increase in polymer hydrophilicity which can explain the absence of a LCST decrease in poly(N,N-diethylacrylamide), water, and methanol systems. The coarse-grained nature of the models indicates that a mean energetic representation of the system is sufficient to understand the phenomena of LCST decrease.

Numerical insights into the phase diagram of p-atic membranes with spherical topology.

The properties of self-avoiding p-atic membranes restricted to spherical topology have been studied by Monte Carlo simulations of a triangulated random surface model. Spherically shaped p-atic membranes undergo a Kosterlitz-Thouless transition as expected with topology induced mutually repelling disclinations of the p-atic ordered phase. For flexible membranes the phase behaviour bears some resemblance to the spherically shaped case with a p-atic disordered crumpled phase and p-atic ordered, conformationally ordered (crinkled) phase separated by a KT-like transition with proliferation of disclinations. We confirm the proposed buckling of disclinations in the p-atic ordered phase, while the expected associated disordering (crumpling) transition at low bending rigidities is absent in the phase diagram.

Flow-induced nonequilibrium self-assembly in suspensions of stiff, apolar, active filaments.

Active bodies in viscous fluids interact hydrodynamically through self-generated flows. A stiff, apolar, active filament generates symmetric fluid flow around it and thus cannot self-propel. Here we study the mobility and aggregation induced by hydrodynamic flow in a suspension of stiff, apolar, active filaments. We consider two types of active filaments, with those producing extensile or contractile flows along their long axis. Lateral hydrodynamic attractions in extensile filaments lead, independent of the volume fraction, to anisotropic aggregates which translate and rotate ballistically. Lateral hydrodynamic repulsions in contractile filaments lead to microstructured states, where the degree of clustering increases with the volume fraction and the filament motion is always diffusive. Our results demonstrate that the interplay between active hydrodynamic flows and anisotropic excluded volume interactions provides a generic nonequilibrium mechanism for hierarchical self-assembly of active soft matter.

Curvature inducing macroion condensation driven shape changes of fluid vesicles.

We study the effect of curvature inducing macroion condensation on the shapes of charged deformable fluid interfaces using dynamically triangulated Monte Carlo simulations. In the weak electrostatic coupling regime, surface charges are weakly screened and the conformations of a vesicle, with fixed spherical topology, depend on the charge-charge interaction on the surface. While in the strong coupling regime, condensation driven curvature induction plays a dominant role in determining the conformations of these surfaces. Condensation itself is observed to be dependent on the induced curvature, with larger induced curvatures favoring increased condensation. We show that both curvature generation and curvature sensing, induced by the interplay of electrostatics and curvature energy, contribute to determination of the vesicle configurations.

Monte Carlo simulations of fluid vesicles.

Lipid vesicles are closed two dimensional fluid surfaces that are studied extensively as model systems for understanding the physical properties of biological membranes. Here we review the recent developments in the Monte Carlo techniques for simulating fluid vesicles and discuss some of their applications. The technique, which treats the membrane as an elastic sheet, is most suitable for the study of large scale conformations of membranes. The model can be used to study vesicles with fixed and varying topologies. Here we focus on the case of multi-component membranes with the local lipid and protein composition coupled to the membrane curvature leading to a variety of shapes. The phase diagram is more intriguing in the case of fluid vesicles having an in-plane orientational order that induce anisotropic directional curvatures. Methods to explore the steady state morphological structures due to active flux of materials have also been described in the context of Monte Carlo simulations.

Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins.

Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across the various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham - Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this description, the protein is expressed in the form of a spontaneous curvature field. The approaches include field theoretical methods limited to the small deformation regime, triangulated surfaces and particle-based computational models to investigate the large-deformation regimes observed in the natural state of many biological membranes. Applications of these methods to understand the properties of biological membranes in homogeneous and inhomogeneous environments of proteins, whose underlying curvature fields are either isotropic or anisotropic, are discussed. The diversity in the curvature fields elicits a rich variety of morphological states, including tubes, discs, branched tubes, and caveola. Mapping the thermodynamic stability of these states as a function of tuning parameters such as concentration and strength of curvature induction of the proteins is discussed. The relative stabilities of these self-organized shapes are examined through free-energy calculations. The suite of methods discussed here can be tailored to applications in specific cellular settings such as endocytosis during cargo trafficking and tubulation of filopodial structures in migrating cells, which makes these methods a powerful complement to experimental studies.

Kinetics of domain registration in multicomponent lipid bilayer membranes.

The kinetics of registration of lipid domains in the apposing leaflets of symmetric bilayer membranes is investigated via systematic dissipative particle dynamics simulations. The decay of the distance between the centres of mass of the domains in the apposing leaflets is almost linear during early stages, and then becomes exponential during late times. The time scales of both linear and exponential decays are found to increase with decreasing strength of interleaflet coupling. The ratio between the time scales of the exponential and linear regimes decreases with increasing domain size, implying that the decay of the distance between the domains' centres of mass is essentially linear for large domains. These numerical results are largely in agreement with the recent theoretical predictions of Han and Haataja [Soft Matter, 2013, 9, 2120-2124]. We also found that the domains become elongated during the registration process.

Predictions of phase separation in three-component lipid membranes by the MARTINI force field.

The phase behavior of the coarse-grained MARTINI model for three-component lipid bilayers composed of dipalmytoyl-phosphatidylcholine (DPPC), cholesterol (Chol), and an unsaturated phosphatidylcholine (PC) was systematically investigated by molecular dynamics simulations. The aim of this study is to understand which types of unsaturated PC induce the formation of thermodynamically stable coexisting phases when added to mixtures of DPPC and Chol and to unravel the mechanisms that drive phase separation in such three-component mixtures. Our simulations indicate that the currently used MARTINI force field does not induce such phase separation in mixtures of DPPC, Chol, and unsaturated PCs with a low unsaturation level, such as palmitoyl-oleoyl-phosphatidylcholine (POPC) or dioleoyl-phosphatidylcholine (DOPC). Also, we found that phase separation does occur in mixtures of DPPC, Chol, and polyunsaturated PCs, such as dilinoleyl-phosphatidylcholine (DUPC) and diarachidonoyl-phosphatidylcholine (DAPC). Through systematic tweaking of the interactions between the hydrophobic groups of the PC molecules, we show that the appearance of phase separation in three-component lipid bilayers, as modeled through the MARTINI force field, is primarily due to the interactions between the coarse-grained molecules, i.e., the beads, rather than due to the differences between the conformations of saturated and unsaturated lipid acyl chains, namely entropy driven.

Membrane-mediated aggregation of curvature-inducing nematogens and membrane tubulation.

The shapes of cell membranes are largely regulated by membrane-associated, curvature-active proteins. Herein, we use a numerical model of the membrane, recently developed by us, with elongated membrane inclusions possessing spontaneous directional curvatures that could be different along, and perpendicular to, the membrane's long axis. We show that, due to membrane-mediated interactions, these curvature-inducing membrane-nematogens can aggregate spontaneously, even at low concentrations, and change the local shape of the membrane. We demonstrate that for a large group of such inclusions, where the two spontaneous curvatures have equal sign, the tubular conformation and sometimes the sheet conformation of the membrane are the common equilibrium shapes. We elucidate the factors necessary for the formation of these protein lattices. Furthermore, the elastic properties of the tubes, such as their compressional stiffness and persistence length, are calculated. Finally, we discuss the possible role of nematic disclination in capping and branching of the tubular membranes.

Stiffness transition in anisotropic fiber nets.

We demonstrate the existence of a percolationlike stiffness transition in fiber networks with a bidisperse orientation distribution and with fiber densities clearly above the geometrical and the ordinary stiffness transition. The fibers are oriented parallel and perpendicular to a strain direction and they have a large fiber aspect ratio. The stiffness K of the fiber nets can be described by a scaling relation, K [proportionally] τ(α) g[(ε - ε(c))/τ(-ß)], where τ is the fraction of fibers parallel to strain. g is a scaling function that is roughly described by a power law g(x) [proportionally ] x(γ) for stiffness above the transition and by a constant below the transition. The transition point is characterized by qualitative changes in the distribution of the elastic deformation energy of the fibers, the deformation mode of the fibers, the effective Poisson ratio of the nets, the distribution of elastic energy on fibers and cross links, and the ratio of elastic and viscous dissipation energy. This transition opens the possibility of extreme stiffness variations with minimal mesh manipulations in the vicinity of the transition (i.e., a stiffness gate). It is possible that this transition affects the mechanical behavior of the cytoskeleton in cells.

Monte Carlo simulations of fluid vesicles with in-plane orientational ordering.

We present a method for simulating fluid vesicles with in-plane orientational ordering. The method involves computation of local curvature tensor and parallel transport of the orientational field on a randomly triangulated surface. It is shown that the model reproduces the known equilibrium conformation of fluid membranes and work well for a large range of bending rigidities. Introduction of nematic ordering leads to stiffening of the membrane. Nematic ordering can also result in anisotropic rigidity on the surface leading to formation of membrane tubes.

Implicit-solvent mesoscale model based on soft-core potentials for self-assembled lipid membranes.

An efficient implicit-solvent model for self-assembled lipid bilayers is presented and analyzed using Langevin molecular dynamics simulations. The model is based on soft interactions between particles and short-range attractive interaction between lipid tails, leading for the self-assembly of a lipid bilayer without an explicit solvent. This allows for efficient simulations of large membranes over long times. The model exhibits a fluid phase at high temperatures and a gel phase at low temperatures, identified with the Lbeta-phase. The melting transition is investigated via analysis of the diffusivity of the lipid molecules, the chain-orientational order parameter, the sixfold bond-orientational order parameter, and the positional and bond-orientational correlation functions. The analysis suggests the existence of a hexatic phase over a narrow range of temperatures around the melting transition. The elastic properties of the membrane in the fluid phase are also investigated.

A Lattice-Boltzmann model for suspensions of self-propelling colloidal particles.

We present a Lattice-Boltzmann method for simulating self-propelling (active) colloidal particles in two dimensions. Active particles with symmetric and asymmetric force distribution on their surface are considered. The velocity field generated by a single active particle, changing its orientation randomly, and the different time scales involved are characterized in detail. The steady-state speed distribution in the fluid, resulting from the activity, is shown to deviate considerably from the equilibrium distribution.

Domain growth, budding, and fission in phase-separating self-assembled fluid bilayers.

A systematic investigation of the phase-separation dynamics in self-assembled binary fluid vesicles and open membranes is presented. We use large-scale dissipative particle dynamics to explicitly account for solvent, thereby allowing for numerical investigation of the effects of hydrodynamics and area-to-volume constraints. In the case of asymmetric lipid composition, we observed regimes corresponding to coalescence of flat patches, budding, vesiculation, and coalescence of caps. The area-to-volume constraint and hydrodynamics have a strong influence on these regimes and the crossovers between them. In the case of symmetric mixtures, irrespective of the area-to-volume ratio, we observed a growth regime with an exponent of 1/2. The same exponent is also found in the case of open membranes with symmetric composition.

Dynamics of domain growth in self-assembled fluid vesicles.

The dynamics of phase separation in multicomponent bilayer fluid vesicles is investigated by means of large-scale dissipative particle dynamics. The model explicitly accounts for solvent particles, thereby allowing for the very first numerical investigation of the effects of hydrodynamics and area-to-volume constraints. We observed regimes corresponding to coalescence of flat patches, budding and vesiculation, and coalescence of caps. We point out that the area-to-volume constraint has a strong influence on crossovers between these regimes.

Scale invariance in coarsening of binary and ternary fluids.

Phase separation in binary and ternary fluids is studied using a two-dimensional lattice gas automata. The lengths given by the the first zero crossing point of the correlation function and the total interface length is shown to exhibit power law dependence on time. In binary mixtures, our data clearly indicate the existence of a regime having more than one length scale, where the coarsening process proceeds through the rupture and reassociation of domains. In ternary fluids; in the case of symmetric mixtures there exists a regime with a single length scale having dynamic exponent 1/2, while in asymmetric mixtures our data establish the break down of scale invariance.

Two-component fluid membranes near repulsive walls: Linearized hydrodynamics of equilibrium and nonequilibrium states.

We study the linearized hydrodynamics of a two-component fluid membrane near a repulsive wall, using a model that incorporates curvature-concentration coupling as well as hydrodynamic interactions. This model is a simplified version of a recently proposed one [J.-B. Manneville et al., Phys. Rev. E 64, 021908 (2001)] for nonequilibrium force centers embedded in fluid membranes, such as light-activated bacteriorhodopsin pumps incorporated in phospholipid egg phosphatidyl choline (EPC) bilayers. The pump-membrane system is modeled as an impermeable, two-component bilayer fluid membrane in the presence of an ambient solvent, in which one component, representing active pumps, is described in terms of force dipoles displaced with respect to the bilayer midpoint. We first discuss the case in which such pumps are rendered inactive, computing the mode structure in the bulk as well as the modification of hydrodynamic properties by the presence of a nearby wall. These results should apply, more generally, to equilibrium fluid membranes comprised of two components, in which the effects of curvature-concentration coupling are significant, above the threshold for phase separation. We then discuss the fluctuations and mode structure in the steady state of active two-component membranes near a repulsive wall. We find that proximity to the wall smoothens membrane height fluctuations in the stable regime, resulting in a logarithmic scaling of the roughness even for initially tensionless membranes. This explicitly nonequilibrium result is a consequence of the incorporation of curvature-concentration coupling in our hydrodynamic treatment. This result also indicates that earlier scaling arguments which obtained an increase in the roughness of active membranes near repulsive walls upon neglecting the role played by such couplings may need to be reevaluated.

Budding dynamics of multicomponent membranes.

The budding of multicomponent membranes is studied by computer simulations and scaling arguments. The simulation algorithm combines dynamic triangulation with Kawasaki exchange dynamics. The budding process exhibits three distinct time regimes: (i) formation and growth of intramembrane domains; (ii) formation of many buds; and (iii) coalescence of small buds into larger ones. The coalescence regime (iii) is characterized by scaling laws which describe the long-time behavior. Thus, the number of buds, N(bud), decays as N(bud) approximately 1/t(theta) for large time t with theta = 1/2 and theta = 2/3 in the absence and the presence of hydrodynamic interactions, respectively.

Modulated phases in multicomponent fluid membranes.

We investigate the behavior of flexible two-component bilayer and three-component monolayer membranes. The components are assumed to have different spontaneous curvatures, and to mutually phase separate in planar membranes. As a function of temperature, lateral tension and bending rigidity, a rich phase behavior is obtained. In particular, we find three different types of modulated phases. In symmetric bilayers, the excess component assembles at the boundary between oppositely curved domains; in sufficiently asymmetric bilayers, the excess component is found to preferentially assemble in a single layer, with no tendency for segregation to the domain boundaries. We show that the phase behavior of three-component monolayer strongly resembles the behavior of two-component bilayers. In fact, in a certain, restricted region of parameter space, the two models can be shown to be equivalent.