Matthew I. Hoopes

Coarse-grained modeling of lipids.

Molecular modeling of phospholipids on many scales has progressed significantly over the last years. Here we review several membrane models on intermediate to large length scales restricting ourselves to particle based coarse-grained models with implicit and explicit solvent. We explain similarities and differences as well as their connection to experiments and fine-grained models. We neglect any field descriptions on larger scales. We discuss then a few examples where we focus on studies of lipid phase behavior as well as supported lipid bilayers as these examples can only be meaningfully studied using large-scale models to date.

Bilayer Structure and Lipid Dynamics in a Model Stratum Corneum with Oleic Acid

The stratum corneum is the uppermost layer of the skin and acts as a barrier to keep out contaminants and retain moisture. Understanding the molecular structure and behavior of this layer will provide guidance for optimizing its biological function. In this study we use a model mixture comprised of equimolar portions of ceramide NS (24:0), lignoceric acid, and cholesterol to model the effect of the addition of small amounts of oleic acid to the bilayer at 300 and 340 K. Five systems at each temperature have been simulated with concentrations between 0 and 0.1 mol % oleic acid. Our major finding is that subdiffusive behavior over the 200 ns time scale is evident in systems at 340 K, with cholesterol diffusion being enhanced with increased oleic acid. Importantly, cholesterol and other species diffuse faster when radial densities indicate nearest neighbors include more cholesterol. We also find that, with the addition of oleic acid, the bilayer midplane and interfacial densities are reduced and there is a 3% decrease in total thickness occurring mostly near the hydrophilic interface at 300 K with reduced overall density at 340 K. Increased interdigitation occurs independent of oleic acid with a temperature increase. Slight ordering of the long non-hydroxy fatty acid of the ceramide occurs near the hydrophilic interface as a function of the oleic acid concentration, but no significant impact on hydrogen bonding is seen in the chosen oleic acid concentrations.

Coarse-grained modeling of interactions of lipid bilayers with supports

We characterize the differences between supported and unsupported lipid bilayer membranes using a mesoscopic simulation model and a simple particle-based realization for a flat support on to which the lipids are adsorbed. We show that the nanometer roughness of the support affects membrane binding strength very little. We then compare the lipid distributions and pressure profiles of free and supported membranes. The surface localization of the proximal leaflet breaks the symmetry seen in a free bilayer, and we quantify the entropic penalty for binding and the increased lateral compression modulus.

Silica xerogel/aerogel-supported lipid bilayers: consequences of surface corrugation.

The objective of this paper was to review our recent investigations of silica xerogel and aerogel-supported lipid bilayers. These systems provide a format to observe relationships between substrate curvature and supported lipid bilayer formation, lipid dynamics, and lipid mixtures phase behavior and partitioning. Sensitive surface techniques such as quartz crystal microbalance and atomic force microscopy are readily applied to these systems. To inform current and future investigations, we review the experimental literature involving the impact of curvature on lipid dynamics, lipid and phase-separated lipid domain localization, and membrane-substrate conformations and we review our molecular dynamics simulations of supported lipid bilayers with the atomistic and molecular information they provide.

Molecular dynamics simulations of DPPC/CTAB monolayers at the air/water interface.

An atomistic-level understanding of cationic lipid monolayers is essential for development of gene delivery agents based on cationic micelle-like structures. We employ molecular dynamics (MD) simulations for a detailed atomistic study of lipid monolayers composed of both pure zwitterionic dipalmitoylphosphatidylcholine (DPPC) and a mixture of DPPC and cationic cetyltrimethylammonium bromide (CTAB) at the air/water interface. We aim to investigate how the composition of the DPPC/CTAB monolayers affects their structural and electrostatic properties in the liquid-expanded phase. By varying the molar fraction of CTAB, we found the cationic CTAB lipids have significant condensing effect on the DPPC/CTAB monolayers, i.e., at the same surface tension or surface pressure, monolayers with higher CTAB molar fraction have smaller area per lipid. The DPPC/CTAB monolayers are also able to achieve negative surface tension without introducing buckling into the monolayer structure. We also found the condensing effect is caused by the interplay between the cationic CTAB headgroups and the zwitterionic phosphatidylcholine (PC) headgroups which has electrostatic origin. With CTAB in its vicinity, the P-N vector of PC headgroups reorients from being parallel to the monolayer plane to a more vertical orientation. Moreover, detailed analysis of the structural properties of the monolayers, such as the density profile analysis, hydrogen bonding analysis, chain order parameter calculations, and radial distribution function calculations were also performed for better understanding of cationic DPPC/CTAB monolayers.

Lipid domain depletion at small localized bends imposed by a step geometry.

Natural processes in biological cells rely on molecules to be in the right place at the right time to maintain the dynamics of living processes. When lipids in bilayer membranes move and mix, they experience kinetic and thermodynamic barriers that affect the time scales of their locations and associations with each other. One of these barriers is that of the membrane shape. Using spin coating as a deposition technique, we formed multilamellar supported lipid bilayers on topologically patterned substrates with defined step rise heights of 13 and 27 nm measured by atomic force microscopy. Each step rise imposed two ridges on the lipid bilayers, and the ridge angles were measured by atomic force microscopy. The lipid composition of this system was 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and cholesterol (4:4:2), doped with a fluorescent lipid, which displays liquid-ordered-liquid-disordered (Lo-Ld) phase coexistence upon cooling to 25 °C. The DPPC-rich Lo domains in the upper bilayers were established to have boundaries and positions that responded to local forces. We found that these Lo domains were depleted at the location of each step rise. We employed an equation for local bending at a ridge and demonstrate that Lo domain densities at each rise correspond to these energies. Remarkably, an energy barrier greater than 1k(B)T is erected at a small deflection (1.3°) from planar geometry at the ridge, resulting in depletion of the majority of the optically visible Lo domains from the step rise. This work provides a means to design substrates that, in conjunction with supported lipid bilayers, provide defined localized topological energy barriers that can be used in biomembrane engineering. It also provides a method for easily analyzing the energetics of cusp-like shapes in cellular membrane structures.

Multiscale Modeling of Supported Lipid Bilayers

Cell membranes consist of a multitude of lipid molecules that serve as a framework for the even greater variety of membrane associated proteins [1–4]. As this highly complex (nonequilibrium) system cannot easily be understood and studied in a controlled way, a wide variety of model systems have been devised to understand the dynamics, structure, and thermodynamics in biological membranes. One such model system is a supported lipid bilayer (SLB), a two-dimensional membrane suspended on a surface. SLBs have been realized to be manageable experimentally while reproducing many of the key features of real biological membranes [5,6]. One of the main advantages of supported bilayers is the physical stability due to the solid support that enables a wide range of surface characterization techniques not available to free or unsupported membranes. As SLBs maintain some of the crucial structural and dynamic properties of biological membranes, they provide an important bridge to natural systems. In order to mimic cell membranes reliably, certain structural and dynamic features have to be reliably reproduced in the artificially constructed lipid bilayers. SLBs should display lateral mobility as in living cells, because many membrane activities involve transport, recruitment, or assembly of specific components. It is also critical for membranes to exhibit the correct thermodynamic phase, namely, a fluid lipid bilayer, to respond to environmental stress such as temperature and pressure changes [7]. There are several ways to fabricate supported lipid bilayers (SLBs) on planar substrates. One can use vesicle fusion on solid substrates [5,8–10] as well as Langmuir-Blodgett deposition [11,12]. Proteoliposome adsorption and subsequent membrane formation on a mica surface was first demonstrated by Brian and McConnell [13]. Because of its simplicity and reproducibility, this is one of the most common approaches to prepare supported membranes. A diverse range of different solid substrates has been used as support material below the bilayer [14,15]. Silicon oxide is the material of choice for vesicle fusion [16]. Polymer cushions dampen the effect of hard surfaces and therefore have been actively investigated [17–20]. However, it is not fully understood which changes the introduction of a solid support introduces into such a biomimetic system. Experimentally it is almost impossible to address such changes, as extremely highresolution data would be required.

Membrane Curvature Modeling and Lipid Organization in Supported Lipid Bilayers

Membranes in the cell exist in a wide range of shapes and provide for compartmentalization and transport throughout the cell. Curvature plays an important role in this cellular organization and even the organization of lipids within the membrane itself. Supported lipid bilayers (SLB) continue to be an important means of measuring the thermodynamic and mechanical properties of phospholipid membranes, but on some supports, the proximity of the solid surface may modify the behavior of the adsorbed bilayer. To overcome this problem, we use a technique for spin coating lipids on the substrate that creates multilamellar stacks of membranes[1] where the influence of the substrate on upper layers is weakened. The substrates we have used are nanoscopically patterned with steps and these features induce curvature in the membranes that appear to be step-height dependent. This provides a platform for adhesion, mobility and organizational studies. We show that multilamellar SLB on patterned substrates exhibit curvature induced phase separated domain organization and increased lateral lipid mobility. Molecular dynamics of coarse-grained supported lipid bilayers[2] are used to simulate membranes supported on corrugated surfaces and we discuss and compare the behavior with experimental systems. We show that substrate corrugation height, adhesion energy, and mechanical moduli can be controlled to predict adsorbed membrane curvature. Furthermore we model lipid mixtures in the regions of substrate induced curvature to show the relationship between bending energies and phase separation.[1] M.H. Jensen, E.J. Morris, A.C. Simonsen, Domain Shapes, Coarsening, and Random Patterns in Ternary Membranes, Langmuir 23 (2007) 8135-8141.[2] M.I. Hoopes, M. Deserno, M.L. Longo, R. Faller, Coarse-grained modeling of interactions of lipid bilayers with supports, The Journal of Chemical Physics 129 (2008) 175102-175107.