Molecular mechanism for lipid flip-flops

Transmembrane lipid translocation (flip-flop) processes are involved in a variety of properties and functions of cell membranes, such as membrane asymmetry and programmed cell death. Yet, flip-flops are one of the least understood dynamical processes in membranes. In this work, we elucidate the molecular mechanism of pore-mediated transmembrane lipid translocation (flip-flop) acquired from extensive atomistic molecular dynamics simulations. On the basis of 50 successful flip-flop events resolved in atomic detail, we demonstrate that lipid flip-flops may spontaneously occur in protein-free phospholipid membranes under physiological conditions through transient water pores on a time scale of tens of nanoseconds. While the formation of a water pore is induced here by a transmembrane ion density gradient, the particular way by which the pore is formed is irrelevant for the reported flip-flop mechanism: the appearance of a transient pore (defect) in the membrane inevitably leads to diffusive translocation of lipids through the pore, which is driven by thermal fluctuations. Our findings strongly support the idea that the formation of membrane defects in terms of water pores is the rate-limiting step in the process of transmembrane lipid flip-flop, which, on average, requires several hours. The findings are consistent with available experimental and computational data and provide a view to interpret experimental observations. For example, the simulation results provide a molecular-level explanation in terms of pores for the experimentally observed fact that the exposure of lipid membranes to electric field pulses considerably reduces the time required for lipid flip-flops.     

Novel computational probes of diffusive motion

Self-diffusion constants, D, and the atomic-level processes that produce them have been investigated numerically for the binary-mixture Lennard-Jones (BMLJ) model and for liquid silica as described by the Van Beest-Kramer-Van Santen interaction model. The primary conceptual tool for this study is the joint probability distribution for single particles as a function of initial velocity and positional displacement at a given later instant. Self-diffusion constants can be expressed exactly in terms of this probability function. The numerical simulations for the BMLJ case reveal an unusual temperature effect; in contrast to the high-temperature behavior, particles with high initial velocities experience disproportionate retardation in forward displacement. In the silica modeling simulations, diffusive processes have been compared at constant-temperature "isodiffusive" pairs of states, demonstrating a significant role played by the amount of local tetrahedral order that is present in the medium.     

Emergent behavior in particle-laden microfluidic systems informs strategies for improving cell and particle separations

Colloidal particles placed in an energy landscape interact with each other, giving rise to complex dynamic behavior that affects the ability to process and manipulate suspensions of these particles. Propagating across scales ranging from the local behavior of 10's of particles to non-local behavior encompassing >10(6) particles, these particle interactions are pervasive and challenging to describe quantitatively, especially in the confined environments typical of microfluidic devices. To better understand the effects of particle interactions in this context, we have performed experiments and simulations involving a simple microfluidic device in which hydrodynamic and electrostatic forces are leveraged to concentrate and separate particle mixtures. These investigations reveal the mechanisms underlying the dynamic patterns formed by micron-scale particles as they impinge on a dielectrophoretic force barrier: their tendency to aggregate and recirculate under constant operating conditions, and to reorganize when the operating conditions are changed. The emergent behaviors of these ensembles of interacting particles exhibit features of dynamical frustration and cooperativity that suggest non-intuitive strategies for concentrating and sorting suspensions. Finally, we present a simple analytic model based on hydrodynamic coupling that captures important features of strongly interacting particle suspensions.     

Identifying Protein Conformational Dynamics Using Spin‐label ESR

Spin‐label electron spin resonance (ESR) has emerged as a powerful tool to characterize protein dynamics. One recent advance is the development of ESR for resolving dynamical components that occur or coexist during a biological process. It has been applied to study the complex structural and dynamical aspects of membranes and proteins, such as conformational changes in protein during translocation from cytosol to membrane, conformational exchange between equilibria in response to protein‐protein and protein‐ligand interactions in either soluble or membrane environments, protein oligomerization, and temperature‐ or hydration‐dependent protein dynamics. As these topics are challenging but urgent for understanding the function of a protein on the molecular level, the newly developed ESR methods to capture individual dynamical components, even in low‐populated states, have become a great complement to other existing biophysical tools.     

Dynamical density functional theory and its application to spinodal decomposition

We present an alternative derivation of the dynamical density functional theory for the one-body density profile of a classical fluid developed by Marconi and Tarazona [J. Chem. Phys. 110, 8032 (1999)]. Our derivation elucidates further some of the physical assumptions inherent in the theory and shows that it is not restricted to fluids composed of particles interacting solely via pair potentials; rather it applies to general, multibody interactions. The starting point for our derivation is the Smoluchowski equation and the theory is therefore one for Brownian particles and as such is applicable to colloidal fluids. In the second part of this paper we use the dynamical density functional theory to derive a theory for spinodal decomposition that is applicable at both early and intermediate times. For early stages of spinodal decomposition our nonlinear theory is equivalent to the (generalized) linear Cahn-Hilliard theory, but for later times it incorporates coupling between different Fourier components of the density fluctuations (modes) and therefore goes beyond Cahn-Hilliard theory. We describe the results of calculations for a model (Yukawa) fluid which show that the coupling leads to the growth of a second maximum in the density fluctuations, at a wave number larger than that of the main peak.     

Two-fluid model for the simultaneous flow of colloids and fluids in porous media

To describe the velocities of particles such as ions, protein molecules and colloids dispersed or dissolved in a fluid, it is important to also describe the forces acting on the fluid, including pressure gradients and friction of the fluid with the particles and with the porous media through which the fluid flows. To account for this problem, the use of a two-fluid model is described, familiar in the field of fluid mechanics, extended to include osmotic effects. We show how familiar relationships follow in various situations and give examples of combined fluid/particle transport in neutral and charged membranes driven by a combination of electrostatic, diffusional and pressure forces. The analysis shows how the same modeling framework can be generally used both for multidimensional electrokinetic flow through macroscopic channels and around macroscopic objects, as well as for mean-field modeling of transport through porous media such as gels and membranes.     

NMR studies on how the binding complex of polyisoprenol recognition sequence peptides and polyisoprenols can modulate membrane structure

The glycosyl carrier lipids, dolichylphosphate (C(95)-P) and undecapreylphosphate (C(55)-P) are key molecular players in the synthesis and translocation of complex glycoconjugates across cell membranes. The molecular mechanism of how these processes occur remains a mystery. Failure to completely catalyze C(95)-P-mediated N-linked protein glycosylation is lethal, as are defects in the C(55)-P-mediated synthesis of bacterial cell surface polymers. Our recent NMR studies have sought to understand the role these "super-lipids" play in biosynthetic and translocation pathways, which are of critical importance to problems in human biology and molecular medicine. The PIs can alter membrane structure by inducing in the lamellar phospholipids (PL) bilayer a non-lamellar or hexagonal (Hex(II)) structure. Membrane proteins that bind PIs contain a transmembrane binding motif, designated a PI recognition sequence (PIRS). Herein we review our recent combination of (1)H- and (31)P NMR spectroscopy and energy minimized molecular modeling studies that have determined the preferred orientation of PIs in model phospholipids membranes. They also show that the addition of a PIRS peptide to nonlamellar membranes induced by the PIs can reverse the Hex(II) phase back to a lamellar structure. Our molecular modeling calculations have also shown that as many as five PIRS peptides can bind to a single PI molecule. These findings lead to the hypothesis that the PI-induced Hex(II) structure may have the potential of forming a membrane channel that could facilitate glycoconjugate translocation processes. This is an alternate hypothesis to the possible existence of hypothetical "flippases" to accomplish movement of hydrophilic sugar chains across hydrophobic membranes.     

Flow-induced translocation of polymers through a fluidic channel: a dissipative particle dynamics simulation study

The dynamics of flow-induced translocation of polymers through a fluidic channel has been studied by dissipative particle dynamics (DPD) approach. Unlike implicit solvent models, the many-body energetic and hydrodynamic interactions are preserved naturally by incorporating explicit solvent particles in this approach. The no-slip wall boundary and the adaptive boundary conditions have been implemented in the modified DPD approach to model the hydrodynamic flow within a specific wall structure of fluidic channel and control the particles' density fluctuations. The results show that the average translocation time versus polymer chain length satisfies a power-law scaling of τ ～N(1.152). The conformational changes and translocation dynamics of polymers through the fluidic channel have also been investigated in our simulations, and two different translocation processes, i.e., the single-file and double-folded translocation events, have been observed in detail. These findings may be helpful in understanding the conformational and dynamic behaviors of such polymer and/or DNA molecules during the translocation processes.     

Complex macromolecular dynamics:: I. Estimation technique for time-resolved emission anisotropy ratio of chromophores incorporated into polymer chains

Time-resolved fluorescence emission anisotropy ratios of carbazolyl groups incorporated into polystyrene chains in polyethyleneoxide(PEO)/1,2-dichloroethane mixtures have been measured by the single photon counting method. The fluorescence depolarization method is very excellent to clarify various dynamical modes of polymer chains, and many theoretical and experimental researches have so far been reported in the field of polymer chain dynamics. However there are few reports about the dynamics on the polymer side chain, because the dynamical mechanism of the polymer side chain is very complicated. In this report we tried to analyze the dynamical modes of the polymer side chains by the fluorescence depolarization method. Five dynamical modes of a polymer chain based on the Wöessner model were estimated by our original analytical technique `χ²-map method'. The value of each mode of a polymer side chain was discussed above the overlap concentration (C^*) of PEO and the micro-environments were clarified in the vicinity of the chromophore attached to the polymer side chain.     

Capillary forces between spherical particles floating at a liquid-liquid interface

We study the capillary forces acting on sub-millimeter particles (0.02-0.6 mm) trapped at a liquid-liquid interface due to gravity-induced interface deformations. An analytical procedure is developed to solve the linearized capillary (Young-Laplace) equation and calculate the forces for an arbitrary number of particles, allowing also for a background curvature of the interface. The full solution is expressed in a series of Bessel functions with coefficients determined by the contact angle at the particle surface. For sub-millimeter spherical particles, it is shown that the forces calculated using the lowest order term of the full solution (linear superposition approximation; LSA) are accurate to within a few percents. Consequently the many particle capillary force is simply the sum of the isolated pair interactions. To test these theoretical results, we use video microscopy to follow the motion of individual particles and pairs of interacting particles at a liquid-liquid interface with a slight macroscopic background curvature. Particle velocities are determined by the balance of capillary forces and viscous drag. The measured velocities (and thus the capillary forces) are well described by the LSA solution with a single fitting parameter.     

Collective dynamics of supercooled water close to the liquid-liquid coexistence lines

We report molecular dynamics simulation results for the collective dynamical properties of supercooled bulk water at 180 K at three different densities, corresponding to different phases whose coexistence has recently been discovered in the supercooled regime. In this study, we focus on the behaviour of the longitudinal and transverse current correlation functions and their relative spectra, which we analyze in detail to understand the dynamical processes responsible for the main features observed. Despite the considerable differences in the structure and densities of the three thermodynamic states considered, the obtained current correlation functions show rather similar behaviour in every case. We show that the longitudinal spectra can only be described in terms of three Lorentzian lines, while the accurate reproduction of the transverse spectra requires at least four separate spectral lines. In fact, the behaviour of the peak frequency of the modes necessary to reproduce the spectra as a function of the wavevector indicates in a clear way the nature of the dynamical process. We demonstrate the presence of collective modes associated with the propagation of both longitudinal and transverse sound along with the important contribution of "optical-like" modes, which point out the relevance of localized motions for a right interpretation of the spectral line shape. The wavevector dependence of the relative contributions of the various modes to the total spectral area is also discussed.     

Intraparticle Flow and Plate Height Effects in Liquid Chromatography Stationary Phases

Abstract

Velocity independent plate heights were apparently first recognized for hydrodynamic chromatography columns, packed with nonporous, 115 micron glass beads which were run at reduced mobile phase velocities of 10 to 10,000. Hydrodynamic chromatography separates based on the tendency of small molecules (or particles) to associate with slower moving fluid streamlines near the surfaces of particles, compared to larger molecules which seek faster streamlines. Consequently, the larger molecules elute first. Velocity independent plate heights in liquid chromatography have also been observed for nonadsorbed solutes in paniculate and fibrous stationary phases. These stationary phases have pores which exceed 10^?4 to 10^?5 cm in dimension. The flat plate height is attributed to flow in the channels formed by these large intraparticle spaces. The development of plate height expressions which represent dispersion at interstitial velocities above 10 cm/min are discussed. Explanations of the uncoupling of dispersion from eluent flow rate in continuous stationary phases, membranes, and gigaporous particles is shown to have their origins in the studies of distribution of particles and molecules in hydrodynamic chromatography columns, and to be adequately described by modifications of the van Deemter equation.     

A proposal for a novel evaluation method of the bending velocities of polymer actuators

This paper proposes a novel evaluation method for three types of velocities of the bending processes of polymer actuators. These velocities are the initial, bending, and backtracking velocities, and the method considers three processes of the bending motion. By calculating the time–width differentiation of the displacement of each process, the initial, bending, and backtracking velocities can be evaluated. Δt of 0.1, 1.0, and 10.0 s were considered to be the differentiations of bending displacement, and the initial, bending, and backtracking velocities were calculated to be 2.15, 0.46, and 0.002 mm/s, respectively. By using the method proposed here, we found that the initial velocity at 75%RH is 2.5 times faster than it was at 45%RH by increasing the adsorption of water. Copyright © 2013 John Wiley & Sons, Ltd.     

Phase-space invariants for aggregates of particles: hyperangular momenta and partitions of the classical kinetic energy

Rigorous definitions are presented for the kinematic angular momentum K of a system of classical particles (a concept dual to the conventional angular momentum J), the angular momentum L(xi) associated with the moments of inertia, and the contributions to the total kinetic energy of the system from various modes of the motion of the particles. Some key properties of these quantities are described-in particular, their invariance under any orthogonal coordinate transformation and the inequalities they are subject to. The main mathematical tool exploited is the singular value decomposition of rectangular matrices and its differentiation with respect to a parameter. The quantities introduced employ as ingredients particle coordinates and momenta, commonly available in classical trajectory studies of chemical reactions and in molecular dynamics simulations, and thus are of prospective use as sensitive and immediately calculated indicators of phase transitions, isomerizations, onsets of chaotic behavior, and other dynamical critical phenomena in classical microaggregates, such as nanoscale clusters.     

Insights into the dynamics of evaporation and proton migration in protonated water clusters from Large‐scale Born–Oppenheimer direct dynamics

Large‐scale on‐the‐fly Born–Oppenheimer molecular dynamics simulations using recent advances in linear scaling electronic structure theory and trajectory integration techniques have been performed for protonated water clusters around the magic number (H₂O)_nH⁺, for n = 20 and 21. Besides demonstrating the feasibility and efficiency of the computational approach, the calculations reveal interesting dynamical details. Elimination of water molecules is found to be fast for both cluster sizes but rather insensitive to the initial geometry. The water molecules released acquire velocities compatible with thermal energies. The proton solvation shell changes between the well‐known Eigen and Zundel motifs and is characterized by specific low‐frequency vibrational modes, which have been quantified. The proton transfer mechanism largely resembles that of bulk water but one interesting variation was observed. © 2012 Wiley Periodicals, Inc.     

Mathematical Modeling of Aluminum Diboride Combustion in an Air Flow

A mathematical model and the results of calculating the ignition and combustion of energetic condensed systems based on mono- and polydispersed aluminum diboride particles in air flows in constant-cross-section channels are reported. The kinetic characteristics of the transformations that separate aluminum diboride particles formed by gasification of energetic condensed systems undergo in a high-temperature oxidizing medium were determined using the dependences of the ignition induction period and combustion time on the air temperature and diameter and initial temperature of the particles. These dependences, in turn, were calculated using the model of parallel chemical reactions. The range of combustion conditions corresponding to the initial air temperatures from 300 to 2000 K and Mach numbers in the channel from 0.1 to 1.5 was considered. The influence of the aluminum diboride particle size and of the rate and initial temperature of the air flow on the combustion efficiency was demonstrated. The relationships between the combustion completeness factor of aluminum diboride particles at various initial parameters of the air flow and gasification products of energetic condensed systems at various fuel mixture equivalence ratios, corresponding to the diffusion and kinetic combustion, were determined. The conditions of the transition between the diffusion and kinetic control modes were found.

     

Effects of anharmonicity on nonadiabatic electron transfer: a model

The effect of anharmonicity in the intramolecular modes of a model system for exothermic intramolecular nonadiabatic electron transfer is probed by examining the dependence of the transition probability on the exoergicity. The Franck-Condon factor for the Morse potential is written in terms of the Gauss hypergeometric function both for a ground initial state and for the general case, and comparisons are made between the first-order perturbation theory results for transition probability for harmonic and Morse oscillators. These results are verified with quantum dynamical simulations using wave-packet propagations on a numerical grid. The transition-probability expression incorporating a high-frequency quantum mode and low-frequency medium mode is compared for Morse and harmonic oscillators in different temperature ranges and with various coarse-graining treatments of the delta function from the Fermi golden rule expression. We find that significant deviations from the harmonic approximation are expected for even moderately anharmonic quantum modes at large values of exoergicity. The addition of a second quantum mode of opposite displacement negates the anharmonic effect at small energy change, but in the inverted regime a significantly flatter dependence on exoergicity is predicted for anharmonic modes.     

Modeling Elastic Pore Sensors for Quantitative Single Particle Sizing

An empirically derived model of how the dimensions of an elastic size-tunable pore sensor change with applied membrane stretch is presented. Quantitative modeling of the pore dimensions, in conjugation with a simplified pore resistance model, enabled particle size and translocation velocity profiles to be calculated from the individual particle 'pulse' events, at any membrane stretch. Size analysis of a trimodal suspension, composed of monodisperse 220, 330 and 410 nm particles, gave rise to 3 distinguishable particle peaks with coefficient of variances below 8.2% and average size values within 2.5% of single modal dynamic light scattering measurements. Particle translocation velocity profiles, over the approximate 12 μm pore sensing zone, showed that particles entering the small pore were initially accelerated to velocities approaching 5,000 to 6,000 μm/s. They then rapidly decelerated due to the pore geometry affects on the forces driving particle translocation, being the electric field strength and fluid flow.