Motion Of Individual Molecules Research Articles

Single molecule dynamics in a virtual cell combining a 3-dimensional matrix model with random walks

Recent advances in light microscopy have enabled single molecules to be imaged and tracked within living cells and this approach is impacting our understanding of cell biology. Computer modeling and simulation are important adjuncts to the experimental cycle since they aid interpretation of experimental results and help refine, test and generate hypotheses. Object-oriented computer modeling is particularly well-suited for simulating random, thermal, movements of individual molecules as they interact with other molecules and subcellular structures, but current models are often limited to idealized systems consisting of unit volumes or planar surfaces. Here, a simulation tool is described that combines a 3-dimensional, voxelated, representation of the cell consisting of subcellular structures (e.g. nucleus, endoplasmic reticulum, cytoskeleton, vesicles, and filopodia) combined with numerical floating-point precision simulation of thousands of individual molecules moving and interacting within the 3-dimensional space. Simulations produce realistic time-series video sequences comprising single fluorophore intensities and realistic background noise which can be directly compared to experimental fluorescence video microscopy data sets.

Computational Insight of Phase Transformation and Drug Release Behaviour of Doxycycline-Loaded Ibuprofen-Based In-Situ Forming Gel.

This research investigates the gel formation behaviour and drug-controlling performance of doxycycline-loaded ibuprofen-based in-situ forming gels (DH-loaded IBU-based ISGs) for potential applications in periodontal treatment. The investigation begins by exploring the physical properties and gel formation behaviour of the ISGs, with a particular focus on determining their sustained release capabilities. To gain a deeper understanding of the molecular interactions and dynamics within the ISGs, molecular dynamic (MD) simulations are employed. The effects of adding IBU and DH on reducing surface tension and water tolerance properties, thus affecting molecular properties. The phase transformation phenomenon is observed around the interface, where droplets of ISGs move out to the water phase, leading to the precipitation of IBU around the interface. The optimization of drug release profiles ensures sustained local drug release over seven days, with a burst release observed on the first day. Interestingly, different organic solvents show varying abilities to control DH release, with dimethyl sulfoxide (DMSO) demonstrating superior control compared to N-Methyl-2-pyrrolidone (NMP). MD simulations using AMBER20 software provide valuable insights into the movement of individual molecules, as evidenced by root-mean-square deviation (RMSD) values. The addition of IBU to the system results in the retardation of IBU molecule movement, particularly evident in the DMSO series, with the diffusion constant value of DH reducing from 1.2452 to 0.3372 and in the NMP series from 0.3703 to 0.2245 after adding IBU. The RMSD values indicate a reduction in molecule fluctuation of DH, especially in the DMSO system, where it decreases from over 140 to 40 Å. Moreover, their radius of gyration is influenced by IBU, with the DMSO system showing lower values, suggesting an increase in molecular compactness. Notably, the DH-IBU configuration exhibits stable pairing through H-bonding, with a higher amount of H-bonding observed in the DMSO system, which is correlated with the drug retardation efficacy. These significant findings pave the way for the development of phase transformation mechanistic studies and offer new avenues for future design and optimization formulation in the ISG drug delivery systems field.

A comparative study on the suitability of virtual labs for school chemistry experiments

Even though the concept of the virtual lab is nearly two decades old now, it has started to gain popularity over the last few years. Teachers and students have been using virtual labs to complement experiments done in physical labs or have even used them exclusively based on the circumstances. Demand for these online simulations reached a new height during the worldwide lockdown due to the COVID-19 pandemic. As schools were closed and thus also physical labs, virtual labs became the only mode of conducting experiments for many students. In this study, we addressed the suitability of virtual labs for school chemistry experiments and compared their effectiveness first qualitatively by focusing on both physical and human resources, convenience, cost, safety, and time involved. Then we assessed the effectiveness of virtual labs quantitatively for the topic ‘matter’ and compared that with the traditional physical lab experiments. We also acknowledged the unique features of virtual labs to understand concepts that are difficult or impossible to visualize in regular physical labs, including molecular arrangement, movement of individual molecules, and different atomic models. Our quantitative assessment based on pre-test and post-test revealed that students’ fundamental understanding improved after intervention through virtual labs, as evident from the t-test.

Single-Molecule Tracking Microscopy - A Tool for Determining the Diffusive States of Cytosolic Molecules

Single-molecule localization microscopy probes the position and motions of individual molecules in living cells with tens of nanometer spatial and millisecond temporal resolution. These capabilities make single-molecule localization microscopy ideally suited to study molecular level biological functions in physiologically relevant environments. Here, we demonstrate an integrated protocol for both acquisition and processing/analysis of single-molecule tracking data to extract the different diffusive states a protein of interest may exhibit. This information can be used to quantify molecular complex formation in living cells. We provide a detailed description of a camera-based 3D single-molecule localization experiment, as well as the subsequent data processing steps that yield the trajectories of individual molecules. These trajectories are then analyzed using a numerical analysis framework to extract the prevalent diffusive states of the fluorescently labeled molecules and the relative abundance of these states. The analysis framework is based on stochastic simulations of intracellular Brownian diffusion trajectories that are spatially confined by an arbitrary cell geometry. Based on the simulated trajectories, raw single-molecule images are generated and analyzed in the same way as experimental images. In this way, experimental precision and accuracy limitations, which are difficult to calibrate experimentally, are explicitly incorporated into the analysis workflow. The diffusion coefficient and relative population fractions of the prevalent diffusive states are determined by fitting the distributions of experimental values using linear combinations of simulated distributions. We demonstrate the utility of our protocol by resolving the diffusive states of a protein that exhibits different diffusive states upon forming homo- and hetero-oligomeric complexes in the cytosol of a bacterial pathogen.

Unexpected Crossover in the kinetics of mutarotation in the supercooled region: the role of H-bonds

Intra- and intermolecular studies on the molten L-sorbose have been carried out at variable temperature conditions to determine the crosover temperature (Tc). In addition, isothermal time-dependent FTIR and Raman measurements were performed to probe the pace of mutarotation and activation energy of this reaction in the studied saccharide, which varied from 53–62 kJ/mol up to 177–192 kJ/mol below and above Tc, respectively. To explain the change in activation barrier for the mutarotation a complementary analysis using difference FTIR spectra collected around Tc = 365 K in the hydroxyl region has been done. It was found that the alteration of kinetic parameters and molecular dynamics around Tc are strictly related to the variation in the strength of H-bonds which above Tc are significantly weaken, increasing the freedom of rotation of functional groups and movement of individual molecules. That phenomenon most likely affects the proton transfer, underlying molecular mechanism of mutarotation, which may lead to the significant increase in activation barrier. The new insight into a molecular aspect of the mutarotation around Tc has created an opportunity to better understanding the relationship between physics of condensed matter and the potential role of H-bonds dynamics on the progress of the chemical reaction in highly viscous systems.

Single-Molecule Imaging to Characterize the Transport Mechanism of the Nuclear Pore Complex.

In the eukaryotic cell, a large macromolecular channel, known as the Nuclear Pore Complex (NPC), mediates all molecular transport between the nucleus and cytoplasm. In recent years, single-molecule fluorescence (SMF) imaging has emerged as a powerful tool to study the molecular mechanism of transport through the NPC. More recently, techniques such as single-molecule localization microscopy (SMLM) have enabled the spatial and temporal distribution of cargos, transport receptors and even structural components of the NPC to be determined with nanometre accuracy. In this protocol, we describe a method to study the position and/or motion of individual molecules transiting through the NPC with high spatial and temporal precision.

S1620104 分子動力学法を用いた固体表面におけるサブモノレイヤー液体潤滑膜の拡散現象の解明([S162-01]情報機器メカニクスとヘッドディスクインターフェイス/情報・精密機器のサーボ・スマート制御(1))

Understanding diffusion flow of submonolayer polar liquid lubricant films on solid surfaces is important, as for example it helps us to improve the reliability and durability of hard disk drives. To gain atomic-level insight into such diffusion phenomena, we conducted molecular dynamics (MD) simulations in this paper. We employed hydrogen bonding potentials to model interactions involved by the polar groups of lubricant molecules and thereby successfully reproduced the effects of polar groups on molecular conformation and diffusion speed. By analyzing the conformations and motions of individual molecules which are hardly experimentally observable, we found that, for submonolayer polar liquid films, molecules tend to lie more flat on solid surfaces with decreasing film thickness, resulting in decrease of diffusion coefficients.

Modeling of G-protein-coupled Receptor Signaling Pathways

Modeling of G-protein-coupled Receptor Signaling Pathways

Nucleation in the presence of slow microscopic dynamics

Nucleation of a new thermodynamic phase is often a slow process due to the need to overcome a high free-energy barrier. However, there are other sources of slow dynamics; for example, at high densities/low temperatures, the movement of individual molecules or spins may be slow. Here, we study nucleation in a simple phenomenological model that has this type of slow microscopic dynamics. We do this to better understand how the two sources of slow dynamics interact. We find that as nucleation is intrinsically slow, only very slow microscopic dynamics strongly affect how nucleation occurs. The composition of the nucleus at the top of the nucleation barrier is much less sensitive to slow microscopic dynamics than is the composition of the nucleus once it is postcritical. However, slow dynamics affects not only the rate but also the pathway, which no longer goes over the saddle point in the free energy. We also find that the slow microscopic dynamics can cause sampling problems in an algorithm developed to calculate nucleation rates, and so cause it to predict the rate incorrectly.

Dipole moment and mobility of molecules in nematic liquid crystals of the 4-n-butyl ester of [4′-n-hexyloxyphenyl] benzoic acid in the absence of external orienting fields

Dielectric polarization was studied in a nematic liquid crystal of the 4-n-butyl ester of [4′-n-hexyloxyphenyl] benzoic acid (BE[HOP]BA) in the absence of external orienting fields in the isotropic and mesophase states in a frequency range of 103–107 Hz. In the isotropic melt, three regions of dielectric absorption of a relaxation origin were revealed. It is shown that two of them are related to a reorientation motion of individual molecules about the longitudinal axes (process I) and about the short axes (process II). Processes I and II have relaxation times τ ∼ 10−9 and 10−8 s and activation energies ΔU ∼ 16 and 23 kcal/mol, respectively; the energy of activation of process II in the liquid-crystal phase increases to ΔU ∼ 38 kcal/mol. In the isotropic melt, in addition to processes I and II, process III occurs in the low-frequency range, which is characterized by greater relaxation times τ ∼ 10−7 s and an activation energy ΔU ∼ 28 kcal/mol. In order to establish the nature of process III, temperature dependences of the dipole moments and Kirkwood correlation factor g were studied in both BE[HOP]BA phases. The magnitude of the Kirkwood factor in the isotropic phase of the BE[HOP]BA near the transition temperature from the mesomorphic state (g ∼ 0.88) indicates the retention of the orientational ordering of molecules of the low-molecular liquid crystal and the compensation of their dipole moments intrinsic to the liquid-crystal state. This circumstance suggests that the third process of the relaxation of dipole polarization is due to a cooperative mode of motion of molecules in mesophase nuclei in the isotropic melt.

Numerical Analysis of the Rheology of Polymeric Liquid Crystals. (2nd Report, Shear and Extensional Flow Behavior).

The Doi equations have been directly computed for shear and extensional flow without closure approximations. An extension is imposed on the shear flow plane. It is well-known that for simple shear flow there are three orientation regimes, depending on the magnitude of shear rate; rotational (tumbling), oscillatory (wagging), and stationary (aligning) orientation behaviors. When we add an extension to simple shear flow, the time period of tumbling is increased, while the order parameter in the regime is almost unchanged. In the wagging regime, however, both the time period and the order parameter are increased. Transitions from the tumbling and wagging regimes to the aligning regime are induced when more than a certain magnitude of extension is imposed on a system. An extension has also an effect to make the first normal stress difference positive. Furthermore, motion of individual molecules has been analyzed by integrating the Langevin equation. It is found that the aligning state in shear and extensional flow is due to an approximately stationary behavior of individual molecules, while the aligning state in simple shear flow is an apparently stationary behavior of a group of many rotational molecules.

Rheo-Dielectric behavior of low molecular weight liquid crystals.

Dielectric relaxation behavior was examined for 4-4′-n-pentyl-cyanobiphenyl (5CB) and 4-4′-n-heptyl-cyanobiphenyl (7CB) under flow. In quiescent states at all temperatures examined, both 5CB and 7CB exhibited dispersions in their complex dielectric constant e*(ω) at characteristic frequencies ω c above 106 rad s–1. This dispersion reflected orientational fluctuation of individual 5CB and 7CB molecules having large dipoles parallel to their principal axis (in the direction of C≡N bond). In the isotropic state at high temperatures, these molecules exhibited no detectable changes of e*(ω) under flow at shear rates \(\). In contrast, in the nematic state at lower temperatures the terminal relaxation intensity of e*(ω) as well as the static dielectric constant e′(0) decreased under flow at \(\). This rheo-dielectric change was discussed in relation to the flow effects on the nematic texture (director distribution) and anisotropy in motion of individual molecules with respect to the director.

Short-range ordering in the supercooled states of a dimer system

The local structural properties in the supercooled liquid and amorphous solid, obtained via fast quenching below the melting point, have been shown to provide important information for understanding the phenomena related to these nonequilibrium states @1,2#. It has been suspected that the conflict between the local close-packing arrangement and the global space-filling placement plays a role in the formation of these disordered states. A geometric consideration of sphere packing helps to illustrate the effect. It has been pointed out by Frank and Kasper @3# that twelve spheres, arranged at the vertices of a regular icosahedron, give the most efficiently closely packed structure around a common center sphere, with each of the outer spheres being surrounded by five other spheres. Such a locally favored structure, however, could not extend to fill up all of space @2#. Indeed, a hierarchy based on the building blocks of spherical geometry is unstable against the long-wavelength orientational fluctuations in flat space @4#. The supercooled state is considered as a state of balance between the local and global preferences and is characterized by a sea of molecules, most of which are connected by fivefold coordinations to their neighbors, mingled with some sixfold or fourfold disclinations. In the equilibrium state, such local structures yield to form a globally ordered crystal where sixfold and fourfold symmetry dominate. The effect of ‘‘geometric frustration’’ has recently been suspected to be responsible for the formation of new amorphous states @5,6#, which is more stable than glassy states at the same temperatures. While such new types of amorphous states may not be unusual in systems of complex molecules @7#, it is worthwhile to examine a system the local geometry of which slightly deviates from the spherical symmetry. In this study, we analyze systematically the short-range orientational as well as translational orders in the quenched states of a dimer system. We examine how the frustration involved in a system with nonspherical local geometries could lead to the formation of amorphous states. It is found that the building blocks based on the detailed geometries of the individual molecules form the basis for the formation of stable structure. The result can still be understood in terms of the concept of geometric frustration. The model system considered in this study consists of 500 rigid dimers in a cubic space, subject to minimum image periodic boundary condition @8#. The molecules interact with each other via a site-site Lennard-Jones potential, 4eN(s/r) 12 2(s/r) 6 O, which mimics certain diatomic molecules with properly chosen bond length b @9#. In our simulation, we choose a small b(50.329s @10#!. We carried out constant-pressure‐constant-enthalpy ~NPH! molecular dynamics simulations on the system, using the extended system method @8#. The translational motion of individual molecules is described by a modified version of Newton’s equation for its center of masses. The rotational motion of each rigid molecule is dictated by the torques generated by the interactions between pairs of atomic sites and is tracked by the time evolution of the transformation matrices between the body frame and the lab frame @8#. The equations of motion were integrated via Gear’s algorithms in a time step of 0.002 t and with an interaction cutoff distance 2.3s. ~In this paper, we use the reduced units defined in terms of the interaction strength e and length s of the Lennard-Jones potential!. The supercooled dimer system considered in this study was quenched in a stepwise manner. With an abrupt lowering of instant temperature by an amount of DT50.025 ~the temperature unit is s/k B) at the beginning of each stage, the system then evolved for 80 time units (t), under an isobaric

Detection of Second-Order Director Fluctuations by Deuteron Spin-Spin Relaxation at a Standard High Field

We report on the measurements of deuteron spin-spin relaxation time T 2 in the nematic phase of MBBA and 5CB using the quadrupolar echo pulse train in a magnetic field of 7 T. The spectral densities J 0 (i) (0) at different carbon sites were derived from the T 2 and T 1 measurements. Using a model that combined rotational diffusion motion of individual molecules and their internal bond rotations, the spectral densities J 1 (i)(ω0) and J 2 (i)(2ω0) could be interpreted, while the measured J 0 (i)(0) were too large. It is argued that second-order director fluctuations contribute in part to the J 0 (i)(0) spectral densities. Thus T 2 measurements at a standard high magnetic field can be used to gain insights on director fluctuations.

Brownian configuration fields: A new method for simulating viscoelastic fluid flow

AbstractIn this paper a new method for calculating viscoelastic fluid flows is presented. The polymer stress is not calculated from a closed form constitutive equation but from a microscopic model. Instead of considering the motion of individual molecules we calculate the evolution of an ensemble of configuration fields, representing the internal degrees of freedom of a model molecule. The configuration fields are deformed and convected by the flow and are exposed to thermal motion. The field description is incorporated in a finite element calculation of the flow field where the stress in the fluid is now obtained from an average taken over all the configuration fields. The results for flow past a cylinder for a Hookean dumbbell suspension will be compared with the results obtained from a fully macroscopic calculation of the equivalent Oldroyd‐B model. Excellent agreement is obtained.

Investigation on the formation behaviour of banded texture in thermotropic main-chain liquid crystalline polymers with linear rod-like and two-dimensional mesogenic units

The mechanism and the formation behaviour of banded texture in non-isothermal processes have been studied for two aromatic main-chain liquid cyrstalline polyesters designated as P(2,8) and PTDT-Br which contain the X-shaped and linear rod-like mesogens along the polymer backbones, respectively. For P(2,8) regular and perfect banded textures were observed within its oriented films which were prepared by shearing in mesomorphic state and subsequent cooling down to room temperature under various conditions. Bandwidth was dependent sensitively on the cooling conditions, about 8 μm for rapid and 2 μm for slow coolings. During the cooling of an oriented film the bands were first generated around 170°C, and their regularity was improved with lowering temperature. The bandwidth as well as the extinction angle of the bands were changed drastically. In such a cooling process the birefringence Δn, the difference between the refractive indices along the shear and lateral directions, of the oriented film was decreased gradually from about 0.06 to 0.03. In the case of PTDT-Br, clear and perfect banded texture could be observed only for the rapid cooling case. The banded formation behaviour was discussed on the basis of a contraction mechanism and it could be explained as the result of zigzag rearrangement of straightforward oriented fibrils under certain contraction effects. The origins of these effects were considered to be the elastic energy stored in the specimens during shearing and the thermal contraction during cooling. The latter was more evident in the rapid cooling case. The orientational relaxation of fibrils or the formation of banded texture occurs during cooling in a small temperature range after an ‘induction stage’, while the relaxation due to free thermal motion of individual molecules may proceed in the whole temperature region before the solidification of specimens.

Diffusive Transport by Breaking Waves

Abstract A simple conceptual model of the relationship between advective transport by breaking waves and diffusive transport is derived. line model postulates that the displacement of fluid parcels by a breaking wave is analogous to molecular diffusion (in a manner similar to conventional mixing length theory). Unlike molecular diffusion, in which the fluctuations of nearby particles are independent, in fluid flow the motion of nearby parcels can be coherent. The effectively random phase of wavebreaking events with respect to an individual particle, however, results in a macroscopic “random walk” of the parcel with a step size related to the width of the breaking wave and a timescale related to the frequency of wave breaking events. As in the case of molecular diffusion, the motion of individual molecules or fluid parcels is unpredictable (chaotic, in fact), but averaging over a large ensemble of parcels results in an ensemble variance that increases linearly with time, formally equivalent to molecular di...

The relationship between antigen concentration, antigen internalization, and antigenic complexes: modeling insights into antigen processing and presentation.

Native antigen is processed and subsequently presented on the surface of antigen-presenting cells, an important step in the elicitation of an immune response. The early events of antigen processing and presentation include: ingestion of a native antigen, intracellular degradation to expose an antigenic peptide fragment, binding of this fragment with an MHC class II molecule, and display of this newly formed complex on the cell surface. Through the development of a mathematical model, a set of mathematical equations which describes the time-dependent appearance, disappearance, and movement of individual molecules, quantitative insight can be gained into the pathways and rate-limiting steps of antigen presentation. The credibility of the model has been verified by comparison to literature data. For example, it has been shown experimentally that macrophages require 60 min for effective antigen presentation, whereas B cells require 6-8 h. The mathematical model predicts these presentation times and identifies the difference in the cell's respective pinocytic rates and sizes as important parameters. B cells capture antigen in their environment through nonspecific fluid-phase pinocytosis as well as by binding antigen to their surface immunoglobulin, allowing receptor-mediated uptake. Uptake of antigen via receptor-mediated endocytosis has been reported to require 1,000-fold less antigen than uptake via nonspecific pinocytosis. The mathematical model clearly predicts this decrease in concentration. The model also makes quantitative predictions for the number of MHC class II-antigen complexes needed to produce T cell stimulation.

Nonlocal electrostatic effects on polar solvation dynamics

A phenomenological theory of polar solvation dynamics in electron transfer that accounts for the spatial- and frequency-dependent dielectric function of the solvent is developed and described in a format appropriate to time-dependent fluorescence Stokes shifts. The basic features of the relaxation dynamics are explored by using various analytical expressions for the dielectric function. The presence of spatial correlations persisting to frequencies higher than those corresponding to longitudinal solvent relaxation, τ−1L, yields significant or even substantial decay components with relaxation times shorter than τL. These are associated with motions of individual molecules within the solvent structural network. The implications of these predictions for solvation dynamics in activated charge-transfer processes are noted.

長い一様断面パイプの分子流コンダクタンスの解析と考え方

The old problem on the molecular flow conductance in a long conduit pipe with a uniform cross sections was analyzed by using a concept of gas diffusion process in a uniform medium. This problem was first treated by Knudsen giving a famous approximate expression for the molecular flow conductance and, after a year, Smoluchowski has given a rigorous expression by summing up motions of individual molecules. In this report, a trial was made to understand molecular flow in a conduit pipe as one of the diffusion processes. It turned out that the well known expression of diffusion coefficient (D=1/3·υλ) did not apply to the problem. A careful consideration has given a more rigorous expression of diffusion coefficient, i.e.D=1/2·υ (l cos θ) 2/lwhere l and l2 are the average and average square of free paths of gas molecules and θ is the angle between l and molecular density gradient. By using the above expression, one can treat the molecular flow as an diffusion process and can obtain the regorous expression of molecular flow conductance.