Nanoscale dynamics of the cadherin-catenin complex bound to vinculin revealed by neutron spin echo spectroscopy.

We report a neutron spin echo (NSE) study of the nanoscale dynamics of the cell-cell adhesion cadherin-catenin complex bound to vinculin. Our measurements and theoretical physics analyses of the NSE data reveal that the dynamics of full-length α-catenin, ß-catenin, and vinculin residing in the cadherin-catenin-vinculin complex become activated, involving nanoscale motions in this complex. The cadherin-catenin complex is the central component of the cell-cell adherens junction (AJ) and is fundamental to embryogenesis, tissue wound healing, neuronal plasticity, cancer metastasis, and cardiovascular health and disease. A highly dynamic cadherin-catenin-vinculin complex provides the molecular dynamics basis for the flexibility and elasticity that are necessary for the AJs to function as force transducers. Our theoretical physics analysis provides a way to elucidate these driving nanoscale motions within the complex without requiring large-scale numerical simulations, providing insights not accessible by other techniques. We propose a three-way "motorman" entropic spring model for the dynamic cadherin-catenin-vinculin complex, which allows the complex to function as a flexible and elastic force transducer.

Neutron Instruments for Research in Coordination Chemistry.

Neutron diffraction and spectroscopy offer unique insight into structures and properties of solids and molecular materials. All neutron instruments located at the various neutron sources are distinct, even if their designs are based on similar principles, and thus, they are usually less familiar to the community than commercial X-ray diffractometers and optical spectrometers. Major neutron instruments in the USA, which are open to scientists around the world, and examples of their use in coordination chemistry research are presented here, along with a list of similar instruments at main neutron facilities in other countries. The reader may easily and quickly find from this minireview an appropriate neutron instrument for research. The instruments include single-crystal and powder diffractometers to determine structures, inelastic neutron scattering (INS) spectrometers to probe magnetic and vibrational excitations, and quasielastic neutron scattering (QENS) spectrometers to study molecular dynamics such as methyl rotation on ligands. Key and unique features of the diffraction and neutron spectroscopy that are relevant to inorganic chemistry are reviewed.

Computation of X-ray and Neutron Scattering Patterns to Benchmark Atomistic Simulations against Experiments.

Molecular Dynamics simulations study material structure and dynamics at the atomic level. X-ray and neutron scattering experiments probe exactly the same time- and length scales as the simulations. In order to benchmark simulations against measured scattering data, a program is required that computes scattering patterns from simulations with good single-core performance and support for parallelization. In this work, the existing program Sassena is used as a potent solution to this requirement for a range of scattering methods, covering pico- to nanosecond dynamics, as well as the structure from some Ångströms to hundreds of nanometers. In the case of nanometer-level structures, the finite size of the simulation box, which is referred to as the finite size effect, has to be factored into the computations for which a method is described and implemented into Sassena. Additionally, the single-core and parallelization performance of Sassena is investigated, and several improvements are introduced.

Investigation of the Dynamic Behaviour of H2 and D2 in a Kinetic Quantum Sieving System.

Porous organic cages (POCs) are nanoporous materials composed of discrete molecular units that have uniformly distributed functional pores. The intrinsic porosity of these structures can be tuned accurately at the nanoscale by altering the size of the porous molecules, particularly to an optimal size of 3.6 Å, to harness the kinetic quantum sieving effect. Previous research on POCs for isotope separation has predominantly centered on differences in the quantities of adsorbed isotopes. However, nuclear quantum effects also contribute significantly to the dynamics of the sorption process, offering additional opportunities for separating H2 and D2 at practical operational temperatures. In this study, our investigations into H2 and D2 sorption on POC samples revealed a higher uptake of D2 compared to that of H2 under identical conditions. We employed quasi-elastic neutron scattering to study the diffusion processes of D2 and H2 in the POCs across various temperature and pressure ranges. Additionally, neutron Compton scattering was utilized to measure the values of the nuclear zero-point energy of individual isotopic species in D2 and H2. The results indicate that the diffusion coefficient of D2 is approximately one-sixth that of H2 in the POC due to the nuclear quantum effect. Furthermore, the results reveal that at 77 K, D2 has longer residence times compared to H2 when moving from pore to pore. Consequently, using the kinetic difference of H2 and D2 in a porous POC system enables hydrogen isotope separation using a temperature or pressure swing system at around liquid nitrogen temperatures.

Atomic diffusion in liquid gallium and gallium-nickel alloys probed by quasielastic neutron scattering and molecular dynamic simulations.

The atomic mobility in liquid pure gallium and a gallium-nickel alloy with 2 at% of nickel is studied experimentally by incoherent quasielastic neutron scattering. The integral diffusion coefficients for all-atom diffusion are derived from the experimental data at different temperatures. DFT-basedab-initiomolecular dynamics (MD) is used to find numerically the diffusion coefficient of liquid gallium at different temperatures, and numerical theory results well agree with the experimental findings at temperatures below 500 K. Machine learning force fields derived fromab-initiomolecular dynamics (AIMD) overestimate within a small 6% error the diffusion coefficient of pure gallium within the genuine AIMD. However, they better agree with experiment for pure gallium and enable the numerical finding of the diffusion coefficient of nickel in the considered melted alloy along with the diffusion coefficient of gallium and integral diffusion coefficient, that agrees with the corresponding experimental values within the error bars. The temperature dependence of the gallium diffusion coefficientDGa(T)follows the Arrhenius law experimentally for all studied temperatures and below 500 K also in the numerical simulations. However,DGa(T)can be well described alternatively by an Einstein-Stokes dependence with the metallic liquid viscosity following the Arrhenius law, especially for the MD simulation results at all studied temperatures. Moreover, a novel variant of the excess entropy scaling theory rationalized our findings for gallium diffusion. Obtained values of the Arrhenius activation energies are profoundly different in the competing theoretical descriptions, which is explained by different temperature-dependent prefactors in the corresponding theories. The diffusion coefficient of gallium is significantly reduced (at the same temperature) in a melted alloy with natural nickel, even at a tiny 2 at% concentration of nickel, as compared with its pure gallium value. This highly surprising behavior contradicts the existing excess entropy scaling theories and opens a venue for further research.

Quasielastic Neutron Scattering Study on Thermal Gelation in Aqueous Solution of Agarose.

The dynamics of water and agarose molecules in an agarose aqueous solution has been studied by means of quasielastic neutron scattering (QENS). The dynamic structure factor S (Q,E) of the agarose aqueous solution was fitted well to the sum of the Lorentz and delta function. The former is attributed to the diffusive motion of water molecules and the latter to the local vibrational motion of agarose molecules. The self-diffusion coefficient D of water molecules was obtained from the Q-dependence of the width of the Lorentz function, while the mean square displacement of agarose molecules was obtained from the Q-dependence of the intensity of the delta term. In the cooling direction, both D and decreased with decreasing temperature and showed discontinuous changes around the thermal gelation temperature (around 314 K). In the heating direction, however, D and did not show the obvious change below 343 K, indicating a large hysteresis effect. The present results of and D revealed that the thermal gelation suppresses the motion of the polymer and accelerates the diffusion of water molecules. The activation energy Ea of the diffusion of water in the sol state is the same as that of bulk water, but the Ea in the gel state is clearly smaller than that of bulk water.

Beyond Rattling: Tetrahedrites as Incipient Ionic Conductors.

Materials with ultralow thermal conductivity are crucial to many technological applications, including thermoelectric energy harvesting, thermal barrier coatings, and optoelectronics. Liquid-like mobile ions are effective at disrupting phonon propagation, hence suppressing thermal conduction. However, high ionic mobility leads to the degradation of liquid-like thermoelectric materials under operating conditions due to ion migration and metal deposition at the cathode, hindering their practical application. Here, a new type of behavior, incipient ionic conduction, which leads to ultralow thermal conductivity, while overcoming the issues of degradation inherent in liquid-like materials, is identified. Using neutron spectroscopy and molecular dynamics (MD) simulations, it is demonstrated that in tetrahedrite, an established thermoelectric material with a remarkably low thermal conductivity, copper ions, although mobile above 200 K, are predominantly confined to cages within the crystal structure. Hence the undesirable migration of cations to the cathode can be avoided. These findings unveil a new approach for the design of materials with ultralow thermal conductivity, by exploring systems in which incipient ionic conduction may be present.

Exceptional Hydrogen Diffusion Rate over Ru Nanoparticle-Doped Polar MgO(111) Surface.

Hydrogen (H) conductivity on oxide-based materials is crucially important in fuel cells and related catalysis. Here, this work measures the diffusion rate of H generated from Ru nanoparticles loaded on polar MgO(111) facet particles under H2 at elevated temperatures without moisture and compares it to conventional nonpolar MgO(110) for the first time by in situ quasielastic neutron scattering (QENS). The QENS reveals an exceptional diffusion rate on the polar facet via a proton (H+ ) hopping mechanism, which is an order of magnitude superior to that of typical H+ -conducting oxides. This work attributes this to the unique atomic arrangement of alternate layers of Mg cations and O anions of the polar MgO(111) where the strong electrostatic field of terminal oxygen anions facilitates protonic migration with a lower degree of local covalency.

Exceptionally Fast Ion Diffusion in Block Copolymer-Based Porous Carbon Fibers.

Confined ionic liquids in hydrophilic porous media have disrupted lattices and can be divided into two layers: An immobile ion layer adheres to the pore surfaces, and an inner layer exhibits faster mobility than the bulk. In this work, we report the first study of ionic liquids confined in block copolymer-based porous carbon fibers (PCFs) synthesized from polyacrylonitrile-block-polymethyl methacrylate (PAN-b-PMMA). The PCFs contain a network of unimodal mesopores of 13.6 nm in diameter and contain more hydrophilic surface functional groups than previously studied porous carbon. Elastic neutron scattering shows no freezing point for 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) confined in PCFs down to 20 K. Quasi-elastic neutron scattering (QENS) is used to measure the diffusion of [BMIM]BF4 confined in PCFs, which, surprisingly, is 7-fold faster than in the bulk. The unprecedentedly high ion diffusion remarks that PCFs hold exceptional potential for use in electrochemical catalysis, energy conversion, and storage.

Multiscale lipid membrane dynamics as revealed by neutron spectroscopy.

The plasma membrane is one of the principal structural components of the cell and, therefore, one of the key components of the cellular life. Because the membrane's dynamics links the membrane's structure and function, the complexity and the broad range of the membrane's motions are essential for the enormously diverse functionality of the cell membrane. Even for the main membrane component, the lipid bilayer, considered alone, the range and complexity of the lipid motions are remarkable. Spanning the time scale from sub-picosecond to minutes and hours, the lipid motion in a bilayer is challenging to study even when a broad array of dynamic measurement techniques is employed. Neutron scattering plays a special role among such dynamic measurement techniques, particularly, because it involves the energy transfers commensurate with the typical intra- and inter- molecular dynamics and the momentum transfers commensurate with intra- and inter-molecular distances. Thus, using neutron scattering-based techniques, the spatial and temporal information on the lipid motion can be obtained and analysed simultaneously. Protium vs. deuterium sensitivity and non-destructive character of the neutron probe add to the remarkable prowess of neutron scattering for elucidating the lipid dynamics. Herein we present an overview of the neutron scattering-based studies of lipid dynamics in model membranes, with a discussion of the direct relevance and implications to the real-life cell membranes. The latter are much more complex systems than simple model membranes, consisting of heterogeneous non-stationary domains composed of lipids, proteins, and other small molecules, such as carbohydrates. Yet many fundamental aspects of the membrane behavior and membrane interactions with other molecules can be understood from neutron scattering measurements of the model membranes. For example, such studies can provide a great deal of information on the interactions of antimicrobial compounds with the lipid matrix of a pathogen membrane, or the interactions of drug molecules with the plasma membrane. Finally, we briefly discuss the recently emerging field of neutron scattering membrane studies with a reach far beyond the model membrane systems.

Non-Arrhenius behaviour of nickel self-diffusion in liquid Ni77Si23.

Nickel self-diffusion was measured for a Ni77Si23alloy in the liquid state over a temperature range of about 400 K through quasielastic neutron scattering. At the two lowest temperature points the derived diffusion coefficients deviate from a high-temperature Arrhenius-type behaviour and indicate a change in dynamics above the liquidus temperature. A fit with a power-law temperature dependence as predicted by the mode coupling theory for the liquid to glass transition can describe the diffusion coefficients quite well over the whole measured temperature range. The obtained results agree with predictions from a classical molecular dynamics (MD)-simulation, which evidenced an increasing glass forming ability with increasing silicon content. A crossover to a super-Arrhenius behaviour was reported for metallic glass formers above the liquidus temperature and the here investigated NiSi alloy demonstrates the same signature.

Dynamical Behavior of Disordered Regions in Disease-Related Proteins Revealed by Quasielastic Neutron Scattering.

Background and Objectives: Intrinsically disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) are known to be involved in various human diseases. Since the IDPs/IDRs are fluctuating between many structural substrates, the dynamical behavior of the disease-related IDPs/IDRs needs to be characterized to elucidate the mechanisms of the pathogenesis of the diseases. As protein motions have a hierarchy ranging from local side-chain motions, through segmental motions of loops or disordered regions, to diffusive motions of entire molecules, segmental motions, as well as local motions, need to be characterized. Materials and Methods: Combined analysis of quasielastic neutron scattering (QENS) spectra with the structural data provides information on both the segmental motions and the local motions of the IDPs/IDRs. Here, this method is applied to re-analyze the QENS spectra of the troponin core domain (Tn-CD), various mutants of which cause the pathogenesis of familial cardiomyopathy (FCM), and α-synuclein (αSyn), amyloid fibril formation of which is closely related to the pathogenesis of Parkinson's disease, collected in the previous studies. The dynamical behavior of wild-type Tn-CD, FCM-related mutant Tn-CD, and αSyn in the different propensity states for fibril formation is characterized. Results: In the Tn-CD, the behavior of the segmental motions is shown to be different between the wild type and the mutant. This difference is likely to arise from changes in the intramolecular interactions, which are suggested to be related to the functional aberration of the mutant Tn-CD. In αSyn, concerted enhancement of the segmental motions and the local motions is observed with an increased propensity for fibril formation, suggesting the importance of these motions in fibril formation. Conclusions: Characterization of the segmental motions as well as the local motions is thus useful for discussing how the changes in dynamical behavior caused by the disease-related mutations and/or environmental changes could be related to the functional and/or behavioral aberrations of these proteins.

Water Dynamics in Cancer Cells: Lessons from Quasielastic Neutron Scattering.

The severity of the cancer statistics around the globe and the complexity involving the behavior of cancer cells inevitably calls for contributions from multidisciplinary areas of research. As such, materials science became a powerful asset to support biological research in comprehending the macro and microscopic behavior of cancer cells and untangling factors that may contribute to their progression or remission. The contributions of cellular water dynamics in this process have always been debated and, in recent years, experimental works performed with Quasielastic neutron scattering (QENS) brought new perspectives to these discussions. In this review, we address these works and highlight the value of QENS in comprehending the role played by water molecules in tumor cells and their response to external agents, particularly chemotherapy drugs. In addition, this paper provides an overview of QENS intended for scientists with different backgrounds and comments on the possibilities to be explored with the next-generation spectrometers under construction.

The dynamical Matryoshka model: 3. Diffusive nature of the atomic motions contained in a new dynamical model for deciphering local lipid dynamics.

In accompanying papers [Bicout et al., BioRxiv https://doi.org/10.1101/2021.09.21.461198 (2021); Cissé et al., BioRxiv https://doi.org/10.1101/2022.03.30.486370 (2022)], a new model called Matryoshka model has been proposed to describe the geometry of atomic motions in phospholipid molecules in bilayers and multilamellar vesicles based on their quasielastic neutron scattering (QENS) spectra. Here, in order to characterize the relaxational aspects of this model, the energy widths of the QENS spectra of the samples were analyzed first in a model-free way. The spectra were decomposed into three Lorentzian functions, which are classified as slow, intermediate, and fast motions depending on their widths. The analysis provides the diffusion coefficients, residence times, and geometrical parameters for the three classes of motions. The results corroborate the parameter values such as the amplitudes and the mobile fractions of atomic motions obtained by the application of the Matryoshka model to the same samples. Since the current analysis was carried out independently of the development of the Matryoshka model, the present results enhance the validity of the model. The model will serve as a powerful tool to decipher the dynamics of lipid molecules not only in model systems, but also in more complex systems such as mixtures of different kinds of lipids or natural cell membranes.

Melting and Re-Freezing Leads to Irreversible Changes in the Morphology and Molecular-Level Dynamics of Pfizer-BioNTech COVID-19 Vaccine.

Background and Objectives: As an mRNA-based vaccine, the Pfizer-BioNTech COVID-19 vaccine has stringent cold storage requirements to preserve functionality of the mRNA active ingredient. To this end, lipid components of the vaccine formulation play an important role in stabilizing and protecting the mRNA molecule for long-term storage. The purpose of the current study was to measure molecular-level dynamics as a function of temperature in the Pfizer-BioNTech COVID-19 vaccine to gain microscopic insight into its thermal stability. Materials and Methods: We used quasielastic and inelastic neutron scattering to probe (1) the vaccine extracted from the manufacturer-supplied vials and (2) unperturbed vaccine in the original manufacturer-supplied vials. The latter measurement was possible due to the high penetrative power of neutrons. Results: Upon warming from the low-temperature frozen state, the vaccine in its original form exhibits two-step melting, indicative of a two-phase morphology. Once the melting is completed (above 0 °C), vaccine re-freezing cannot restore its original two-phase state. This observation is corroborated by the changes in the molecular vibrational spectra. The molecular-level mobility measured in the resulting single-phase state of the re-frozen vaccine greatly exceeds the mobility measured in the original vaccine. Conclusions: Even a brief melting (above 0 °C) leads to an irreversible alteration of the two-phase morphology of the original vaccine formulation. Re-freezing of the vaccine results in a one-phase morphology with much increased molecular-level mobility compared to that in the original vaccine, suggesting irreversible deterioration of the vaccine's in-storage stability. Neutron scattering can be used to distinguish between the vibrational spectra characteristic of the original and deteriorated vaccines contained in the unperturbed original manufacturer-supplied vials.

Ni self-diffusion in glass forming Pd-Ni-S melts.

The Ni self-diffusion in glass forming Pd40Ni40S20, Pd37Ni37S26and Pd31Ni42S27melts was probed by incoherent, quasielastic neutron scattering over a temperature range between 773 and 1023 K. The Ni self-diffusion coefficients are on a 10-10 m2 s-1-10-9 m2 s-1scale and barely change with composition. Each composition exhibits an Arrhenius-type temperature dependence of the Ni self-diffusion coefficients, which results in activation energies ranging fromEA= 348 ± 16 meV for Pd40Ni40S20toEA= 387 ± 6 meV for Pd37Ni37S26. The structural relaxation shows a stretched exponential behavior even far above the liquidus temperatures. In addition, the viscosity of the Pd37Ni37S26melt was measured under reduced gravity conditions. The diffusion calculated from the viscosity reveals a significant deviation from the measured Ni self-diffusion by a factor between 4 and 8. This may indicate a dynamic decoupling between the atoms within the Pd-Ni-S equilibrium melts.

Dynamic Processes and Mechanisms Involved in Relaxations of Single-Chain Nano-Particle Melts.

We present a combined study by quasielastic neutron scattering (QENS), dielectric and mechanical spectroscopy, calorimetry and wide-angle X-ray diffraction on single-chain nano-particles (SCNPs), using the corresponding linear precursor chains as reference, to elucidate the impact of internal bonds involving bulky cross-links on the properties of polymer melts. Internal cross-links do not appreciably alter local properties and fast dynamics. This is the case of the average inter-molecular distances, the ß-relaxation and the extent of the atomic displacements at timescales faster than some picoseconds. Contrarily, the α-relaxation is slowed down with respect to the linear precursor, as detected by DSC, dielectric spectroscopy and QENS. QENS has also resolved broader response functions and stronger deviations from Gaussian behavior in the SCNPs melt, hinting at additional heterogeneities. The rheological properties are also clearly affected by internal cross-links. We discuss these results together with those previously reported on the deuterated counterpart samples and on SCNPs obtained through a different synthesis route to discern the effect of the nature of the cross-links on the modification of the diverse properties of the melts.

Self-diffusion in single component liquid metals: a case study of mercury.

We report the temperature dependent atomic dynamics in mercury investigated with quasi-elastic neutron scattering between 240 and 350 K. The self-diffusivity follows an Arrhenius behavior over the entire investigated temperature range, with an activation energy of 41.8 ± 1.4 meV. The standard deviation is in the order of 5%, significantly more precise than previously reported measurements in the literature. Similar to alkali metal melts, the self-diffusion coefficient close to the melting point can be predicted with an effective atom radius of 1.37 Å. This shows a dominant contribution from the repulsive part of the interatomic potential to the mass transport. We observed deviations from the Stokes/Sutherland-Einstein relation and indications of an increasing collective nature of the dynamics with decreasing temperature. Thus, a transport mechanism of uncorrelated binary collisions cannot fully describe the temperature dependence of the self-diffusion.

Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine.

A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. Here, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.

How Useful can the Voigt Profile be in Protein Folding Processes?

The analytical expression for the Voigt profile, along with its simplified forms for the Gaussian and Lorentzian dominance, is presented. The applicability of the Voigt profile in the description of anomalous diffusion phenomena, ubiquitous in different fields of science including protein folding, is discussed. It is shown that the Voigt profile is a good descriptor of the processes occurring in protein folding and in the native state. The usefulness of the Voigt profile in deriving important information of the diffusive motions in proteins from a quasielastic incoherent neutron scattering experiments is illustrated.