Publications

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Cell membranes are dynamic substrates that achieve a diverse array of functions through multi-scale reconfigurations. We explore the morphological changes that occur upon protein interaction to model membrane systems that induce deformation of their planar structure to yield nanotube assemblies. In the two examples shown in this report we will describe the use of membrane adhesion and particle trajectory to form lipid nanotubes via mechanical stretching, and protein adsorption onto domains and the induction of membrane curvature through steric pressure. Through this work the relationship between membrane bending rigidity, protein affinity, and line tension of phase separated structures were examined and their relationship in biological membranes explored.

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This highly interdisciplinary team has developed dual-color, total internal reflection microscopy (TIRF-M) methods that enable us to optically detect and track in real time protein migration and clustering at membrane interfaces. By coupling TIRF-M with advanced analysis techniques (image correlation spectroscopy, single particle tracking) we have captured subtle changes in membrane organization that characterize immune responses. We have used this approach to elucidate the initial stages of cell activation in the IgE signaling network of mast cells and the Toll-like receptor (TLR-4) response in macrophages stimulated by bacteria. To help interpret these measurements, we have undertaken a computational modeling effort to connect the protein motion and lipid interactions. This work provides a deeper understanding of the initial stages of cellular response to external agents, including dynamics of interaction of key components in the signaling network at the 'immunological synapse,' the contact region of the cell and its adversary.

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We have conducted a molecular dynamics (MD) simulation study of water confined between methyl-terminated and carboxyl-terminated alkylsilane self-assembled monolayers (SAMs) on amorphous silica substrates. In doing so, we have investigated the dynamic and structural behavior of the water molecules when compressed to loads ranging from 20 to 950 MPa for two different amounts of water (27 and 58 water molecules/nm{sup 2}). Within the studied range of loads, we observe that no water molecules penetrate the hydrophobic region of the carboxyl-terminated SAMs. However, we observe that at loads larger than 150 MPa water molecules penetrate the methyl-terminated SAMs and form hydrogen-bonded chains that connect to the bulk water. The diffusion coefficient of the water molecules decreases as the water film becomes thinner and pressure increases. When compared to bulk diffusion coefficients of water molecules at the various loads, we found that the diffusion coefficients for the systems with 27 water molecules/nm{sup 2} are reduced by a factor of 20 at low loads and by a factor of 40 at high loads, while the diffusion coefficients for the systems with 58 water molecules/nm{sup 2} are reduced by a factor of 25 at all loads.

A molecular-scale interpretation of interfacial processes is often downplayed in the analysis of traditional water treatment methods. However, such an approach is critical for the development of enhanced performance in traditional desalination and water treatments. Water confined between surfaces, within channels, or in pores is ubiquitous in technology and nature. Its physical and chemical properties in such environments are unpredictably different from bulk water. As a result, advances in water desalination and purification methods may be accomplished through an improved analysis of water behavior in these challenging environments using state-of-the-art microscopy, spectroscopy, experimental, and computational methods.

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We present the results of massively parallel molecular dynamics simulations aimed at understanding the nanotribological properties of alkylsilane self-assembled monolayers (SAMs) on amorphous silica. In contrast to studies with opposing flat plates, as found in the bulk of the simulation literature, we use a model system with a realistic AFM tip (radius of curvature ranging from 3 to 30 nm) in contact with a SAM-coated silica substrate. We compare the differences in response between systems in which chains are fully physisorbed, fully chemisorbed, and systems with a mixture of the two. Our results demonstrate that the ubiquitous JKR and DMT models do not accurately describe the contact mechanics of these systems. In shear simulations, we find that the chain length has minimal effects on both the friction force and coefficient. The tip radius affects the friction force only (i.e., the coefficient is unchanged) by a constant shift in magnitude due to the increase in pull-off force with increasing radius. We also find that at extremely low loads, on the order of 10 nN, shearing from the tip causes damage to the physisorbed monolayers by removal of molecules. © 2008 American Chemical Society.

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A suite of experimental nuclear magnetic resonance (NMR) spectroscopy tools were developed to investigate lipid structure and dynamics in model membrane systems. By utilizing both multinuclear and multidimensional NMR experiments a range of different intra- and inter-molecular contacts were probed within the membranes. Examples on pure single component lipid membranes and on the canonical raft forming mixture of DOPC/SM/Chol are presented. A unique gel phase pretransition in SM was also identified and characterized using these NMR techniques. In addition molecular dynamics into the hydrogen bonding network unique to sphingomyelin containing membranes were evaluated as a function of temperature, and are discussed.

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We have enhanced our parallel molecular dynamics (MD) simulation software LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator, lammps.sandia.gov) to include many new features for accelerated simulation including articulated rigid body dynamics via coupling to the Rensselaer Polytechnic Institute code POEMS (Parallelizable Open-source Efficient Multibody Software). We use new features of the LAMMPS software package to investigate rhodopsin photoisomerization, and water model surface tension and capillary waves at the vapor-liquid interface. Finally, we motivate the recipes of MD for practitioners and researchers in numerical analysis and computational mechanics.

The purpose of this project is to develop tools to model and simulate the processes of self-assembly and growth in biological systems from the molecular to the continuum length scales. The model biological system chosen for the study is the tendon fiber which is composed mainly of Type I collagen fibrils. The macroscopic processes of self-assembly and growth at the fiber scale arise from microscopic processes at the fibrillar and molecular length scales. At these nano-scopic length scales, we employed molecular modeling and simulation method to characterize the mechanical behavior and stability of the collagen triple helix and the collagen fibril. To obtain the physical parameters governing mass transport in the tendon fiber we performed direct numerical simulations of fluid flow and solute transport through an idealized fibrillar microstructure. At the continuum scale, we developed a mixture theory approach for modeling the coupled processes of mechanical deformation, transport, and species inter-conversion involved in growth. In the mixture theory approach, the microstructure of the tissue is represented by the species concentration and transport and material parameters, obtained from fibril and molecular scale calculations, while the mechanical deformation, transport, and growth processes are governed by balance laws and constitutive relations developed within a thermodynamically consistent framework.

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There are many important biological processes involving lipid bilayers on times scales beyond that accessible by atomistic simulations. We have developed coarse-grained, bead-spring models of lipid molecules to treat membrane fusion, domain formation and the general physical characteristics of lipid bilayers. A key aspect of these coarse-grained models is that the liquid nature of a bilayer is explicitly present in the simulations; the lipids diffuse far beyond their neighbors in contrast to atomistic simulations. With these models self-assembly into a bilayer starting from a random configuration of lipids and solvent is readily simulated. We have performed extensive simulations to characterize these lipid models in single component lipid bilayers. For a variety of tail lengths, the area per lipid as a function of temperature has been calculated; the liquid-gel transition has been characterized. Models have been developed for a variety of lipids including double bonds in the lipid tails. Simulation results will be presented for fusion and domain formation.

In this study, we perform molecular dynamics simulations of adhesive contact and friction between alkylsilane Si(OH){sub 3}(CX{sub 2}){sub 10}CX{sub 3} and alkoxylsilane Si(OH){sub 2}(CX{sub 2}){sub 10}CX{sub 3} (where X = H or F) self-assembled monolayers (SAMs) on an amorphous silica substrate. The alkylsilane SAMs are primarily hydrogen-bonded or physisorbed to the surface. The alkoxylsilane SAMs are covalently bonded or chemisorbed to the surface. Previously, we studied the chemisorbed systems. In this work, we study the physisorbed systems and compare the tribological properties with the chemisorbed systems. Furthermore, we examine how water at the interface of the SAMs and substrate affects the tribological properties of the physisorbed systems. When less than a third of a monolayer is present, very little difference in the microscopic friction coefficient {mu} or shear stresses is observed. For increasing amounts of water, the values of {mu} and the shear stresses decrease; this effect is somewhat more pronounced for fluorocarbon alkylsilane SAMs than for the hydrocarbon SAMs. The observed decrease in friction is a consequence of a slip plane that occurs in the water as the amount of water is increased. We studied the frictional behavior using relative shear velocities ranging from v = 2 cm/s to 2 m/s. Similar to previously reported results for alkoxylsilane SAMs, the values of the measured stress and {mu} for the alkylsilane SAM systems decrease monotonically with v.

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Understanding the dynamics of the membrane protein rhodopsin will have broad implications for other membrane proteins and cellular signaling processes. Rhodopsin (Rho) is a light activated G-protein coupled receptor (GPCR). When activated by ligands, GPCRs bind and activate G-proteins residing within the cell and begin a signaling cascade that results in the cell's response to external stimuli. More than 50% of all current drugs are targeted toward G-proteins. Rho is the prototypical member of the class A GPCR superfamily. Understanding the activation of Rho and its interaction with its Gprotein can therefore lead to a wider understanding of the mechanisms of GPCR activation and G-protein activation. Understanding the dark to light transition of Rho is fully analogous to the general ligand binding and activation problem for GPCRs. This transition is dependent on the lipid environment. The effect of lipids on membrane protein activity in general has had little attention, but evidence is beginning to show a significant role for lipids in membrane protein activity. Using the LAMMPS program and simulation methods benchmarked under the IBIG program, we perform a variety of allatom molecular dynamics simulations of membrane proteins.

The effective interactions between two like-charged rods were examined as a function of angle and separation using molecular dynamics simulations. The effect of concentrations of simple and multivalent salts on the electrostatic repulsions and multivalent-ion-induced attractions were determined. It was found that the stable configuration of two rods evolves from isolated rods to aggregated perpendicular rods to aggregated parallel rods as a result of an increase in the multivalent salt. Monovalent salt was found to enhance the attraction near the onset of aggregation, and reduce it at a higher concentration.

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The adhesion between a glassy polymer melt and substrate is studied in the presence of end-grafted chains chemically attached to the substrate surface. Extensive molecular dynamics simulations have been carried out to study the effect of the areal density Σ of tethered chains and tensile pull velocity v on the adhesive failure mechanisms. The initial configurations are generated using a double-bridging algorithm in which new bonds are formed across a pair of monomers equidistant from their respective free ends. This generates new chain configurations that are substantially different than the original two chains such that the systems can be equilibrated in a reasonable amount of cpu time. At the slowest tensile pull velocity studied, a crossover from chain scission to crazing is observed as the coverage increases, while for very large pull velocity, only chain scission is observed. As the coverage increases, the sections of the tethered chains pulled out from the interface form the fibrils of a craze that are strong enough to suppress chain scission, resulting in cohesive rather than adhesive failure. © 2003 Wiley Periodicals, Inc.

The light-driven photocycle of rhodopsin begins the photoreceptor cascade that underlies visual response. In a sequence of events, the retinal covalently attached to the rhodopsin protein undergoes a conformational change that communicates local changes to a global conformational change throughout the whole protein. In turn, the large-scale protein change then activates G-proteins and signal amplification throughout the cell. The nature of this change, involving a coupling between a local process and larger changes throughout the protein, may be important for many membrane proteins. In addition, functional work has shown that this coupling occurs with different efficiency in different lipid settings. To begin to understand the nature of the efficiency of this coupling in different lipid settings, we present a molecular dynamics study of rhodopsin in an explicit dioleoyl-phosphatidylcholine bilayer. Our system was simulated for 40ns and provides insights into the very early events of the visual cascade, before the full transition and activation have occurred. In particular, we see an event near 10ns that begins with a change in hydrogen bonding near the retinal and that leads through a series of coupled changes to a shift in helical tilt. This type of event, though rare on the molecular dynamics time-scale, could be an important clue to the types of coupling that occur between local and large-scale conformational change in many membrane proteins. © 2003 Elsevier Ltd. All rights reserved.

The effect of cross-linker functionality and interfacial bond density on the fracture behavior of highly cross-linked polymer networks bonded to a solid surface is studied using large-scale molecular dynamics simulations. Three different cross-linker functionalities (f = 3, 4, and 6) are considered. The polymer networks are created between two solid surfaces with the number of bonds to the surfaces varying from zero to full bonding to the network. Stress?strain curves are determined for each system from tensile pull and shear deformations. At full interfacial bond density the failure mode is cohesive. The cohesive failure stress is almost identical for shear and tensile modes. The simulations directly show that cohesive failure occurs when the number of interfacial bonds is greater than in the bulk. Decreasing the number of interfacial bonds results in cohesive to adhesive transition consistent with recent experimental results. The correspondence between the stress?strain curves at different f and the sequence of molecular deformations is obtained. The failure stress decreases with smaller f while failure strain increases with smaller f.

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