Design principles for molecular animation.

Molecular visualization is a powerful way to represent the complex structure of molecules and their higher order assemblies, as well as the dynamics of their interactions. Although conventions for depicting static molecular structures and complexes are now well established and guide the viewer's attention to specific aspects of structure and function, little attention and design classification has been devoted to how molecular motion is depicted. As we continue to probe and discover how molecules move - including their internal flexibility, conformational changes and dynamic associations with binding partners and environments - we are faced with difficult design challenges that are relevant to molecular visualizations both for the scientific community and students of cell and molecular biology. To facilitate these design decisions, we have identified twelve molecular animation design principles that are important to consider when creating molecular animations. Many of these principles pertain to misconceptions that students have primarily regarding the agency of molecules, while others are derived from visual treatments frequently observed in molecular animations that may promote misconceptions. For each principle, we have created a pair of molecular animations that exemplify the principle by depicting the same content in the presence and absence of that design approach. Although not intended to be prescriptive, we hope this set of design principles can be used by the scientific, education, and scientific visualization communities to facilitate and improve the pedagogical effectiveness of molecular animation.

Molecular motion behaviors of starch affect starch-polyphenol inclusion complex and digestibility among different stilbenes polyphenol structures.

Starch-polyphenol V-type inclusion complex has become a hot topic due to its anti-digestibility and nutritional function. This paper aimed to explore the molecular motion behavior of starch affects starch-polyphenol inclusion complex and digestibility among different stilbene polyphenol structures (resveratrol (RA), pterostilbene (PB) and polydatin (PD) via the high-pressure homogenization (HPH) and heat moisture treatment (HMT) processes), which represented the fully extended and limited molecular motion behavior of starch, respectively. These results revealed distinct trends in complex formation among different stilbenes polyphenol structures, highlighting RA as particularly conducive to increasing single helix and V-type crystalline structures with the highest resistant starch (RS) content of 28.11 % due to its smaller steric hindrance. Novelty, in HPH environments with extended molecular motion behavior, the steric hindrance and hydrophobicity/CH-π interactions of polyphenols influence complex formation in the order of RA > PB > PD. Conversely, in HMT systems with limited molecular motion behavior, the limited movement of molecules emphasized the importance of hydrogen bond interactions between polyphenols and starch. Thus, the glucoside in PD enhanced its interaction with starch compared to methoxy-modified PB, leading to increased formation of inclusion complex with RS content of 18.61 %. Overall, these findings deepen the understanding of starch-polyphenol interactions.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels-Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization.

A designed anthracene-based monomer for topochemical Diels-Alder cycloaddition polymerization crystallized with head-to-tail arrangement of molecules, as revealed by single-crystal X-ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels-Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels-Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time-dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat-induced reactions.

Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy.

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

Mesoscopic Kinetic Approach of Nonequilibrium Effects for Shock Waves.

A shock wave is a flow phenomenon that needs to be considered in the development of high-speed aircraft and engines. The traditional computational fluid dynamics (CFD) method describes it from the perspective of macroscopic variables, such as the Mach number, pressure, density, and temperature. The thickness of the shock wave is close to the level of the molecular free path, and molecular motion has a strong influence on the shock wave. According to the analysis of the Chapman-Enskog approach, the nonequilibrium effect is the source term that causes the fluid system to deviate from the equilibrium state. The nonequilibrium effect can be used to obtain a description of the physical characteristics of shock waves that are different from the macroscopic variables. The basic idea of the nonequilibrium effect approach is to obtain the nonequilibrium moment of the molecular velocity distribution function by solving the Boltzmann-Bhatnagar-Gross-Krook (Boltzmann BGK) equations or multiple relaxation times Boltzmann (MRT-Boltzmann) equations and to explore the nonequilibrium effect near the shock wave from the molecular motion level. This article introduces the theory and understanding of the nonequilibrium effect approach and reviews the research progress of nonequilibrium behavior in shock-related flow phenomena. The role of nonequilibrium moments played on the macroscopic governing equations of fluids is discussed, the physical meaning of nonequilibrium moments is given from the perspective of molecular motion, and the relationship between nonequilibrium moments and equilibrium moments is analyzed. Studies on the nonequilibrium effects of shock problems, such as the Riemann problem, shock reflection, shock wave/boundary layer interaction, and detonation wave, are introduced. It reveals the nonequilibrium behavior of the shock wave from the mesoscopic level, which is different from the traditional macro perspective and shows the application potential of the mesoscopic kinetic approach of the nonequilibrium effect in the shock problem.

Inflammation-Responsive Nanoagents for Activatable Photoacoustic Molecular Imaging and Tandem Therapies in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) severely lowers the life quality by progressively destructing joint functions and eventually causing permanent disability, representing a pressing public health concern. The pathogenesis of RA includes the excessive production of proinflammatory cytokines and harmful oxygen-derived free radicals, such as nitric oxide (NO), which constitute vital targets for precise diagnosis and effective treatment of RA. In this study, we introduce an advanced nanoagent that integrates the RA microenvironment-activatable photoacoustic (PA) imaging with multitarget synergistic treatment for RA. A highly sensitive organic probe with NO-tunable energy transformation and molecular geometry is developed, which enables strong near-infrared absorption with a turn-on PA signal, and the active intramolecular motion could further boost PA conversion. The probe is coassembled with an inflammation-responsive prodrug to construct the theranostic nanoagent, on which a macrophage-derived cell membrane with natural tropism to the inflammatory sites is camouflaged to improve the targeting ability to inflamed joints. The nanoagent could not only sensitively detect RA and differentiate the severity but also efficiently alleviate RA symptoms and improve joint function. The combination of activatable probe-mediated NO scavenging and on-demand activation of anti-inflammatory prodrug significantly inhibits the proinflammatory factors and promotes macrophage repolarization from M1 to M2 phenotype. This meticulously designed nanoagent ingeniously integrates RA-specific PA molecular imaging with synergistic multitarget therapy, rendering tremendous promise for precise intervention of RA-related diseases.

Investigation on chain segment motions of various starch molecules under different glycerol-water system.

The molecular motion of starch at different glycerol concentrations (0, 20, 50, and 80 %) was investigated using Electron Paramagnetic Resonance (EPR) spectroscopy. Fourier-transform infrared (FTIR) spectroscopy and 1H nuclear magnetic resonance (1H NMR) spectroscopy confirmed that hydroxyl groups at the C2 and C3 positions of glucose units in corn starch (CS), waxy corn starch (WCS), and high amylose corn starch (HCS) were labeled with 4-amino-TEMPO. The crystallinities of CS, WCS, and HCS after spin-labeling decreased from 30.68 % to 3.21 %, 39.36 % to 1.65 %, and 28.54 % to 8.08 %, respectively. The pseudoplastic fluid properties of the spin-labeled starch remained shear-thin at different glycerol concentrations. EPR revealed the fast- and slow-motion components of the spin-labeled starch molecules dispersed in water. At a glycerol concentration of 20 %, the slow-motion component disappeared, indicating a faster rotational motion of the starch chain segments. As the glycerol concentration increased to 50 and 80 %, the rotational motion slowed because of high viscosity. In particular, the mobility of the spin-labeled WCS chains increased owing to easier access of glycerol and water to the branched structure. This study directly observed the dynamics of the molecular behavior of starch in glycerol-water systems.

Massive Molecular Motion in Crystal Leads to an Unexpected Helical Covalent Polymer in a Solid-state Polymerization.

We designed a proline-derived monomer with azide and alkene functional groups to enable topochemical ene-azide cycloaddition (TEAC) polymerization. In its crystal, the monomer forms supramolecular helices along the 'a' axis through various non-covalent interactions. Along the 'c' axis, the molecules arrange themselves head-to-tail in a wave-like pattern, positioning the azide and alkene groups of adjacent molecules in close proximity and anti-parallel orientation, complying with Schmidt's criteria for topochemical reaction. This prearranged configuration was expected to facilitate smooth topochemical polymerization, resulting in a 1,4-triazoline-linked polymer. Upon heating, the monomer underwent TEAC polymerization in a remarkable single-crystal-to-single-crystal fashion, but, to our surprise, it yielded an unexpected covalent helical polymer linked by 1,5-disubstituted triazoline units. Remarkably, the crystal avoids the ready-to-react arrangement for polymerization, but connects monomer molecules within the supramolecular helix through the cycloaddition of azide and alkene groups, even though they are not in close proximity nor in the expected orientation. This unexpected path, involving a substantial 134° rotation of the alkene group, yields hitherto unknown 1,5-disubstituted triazoline product regiospecifically. This study serves as a cautionary reminder that relying solely on topochemical postulates for predicting reactivity can sometimes be misleading.

INEPT and CP transfer efficiencies of dynamic systems in MAS solid-state NMR.

Hartmann-Hahn cross polarization and INEPT polarization transfer are the most popular sequences to increase the polarization of low-γ nuclei in magic-angle spinning solid-state NMR. It is well known that the two methods preferentially lead to polarization transfer in different parts of molecules. Cross polarization works best in rigid segments of the molecule while INEPT-based polarization transfer is efficient in highly mobile segments where (nearly) isotropic motion averages out the dipolar couplings. However, there have only been few attempts to define the time scales of motion that are compatible with cross polarization or INEPT transfer in a more quantitative way. We have used simple isotropic jump models in combination with simulations based on the stochastic Liouville equation to elucidate the time scales of motion that allow either cross polarization or INEPT-based polarization transfer. We investigate which motional time scales interfere with one or both polarization-transfer schemes. We have modeled isolated I-S two-spin systems, strongly-coupled I2S three-spin systems and more loosely coupled I-I-S three-spin systems as well as I3S groups. Such fragments can be used as models for typical environments in fully deuterated and back-exchanged molecules (I-S), for fully protonated molecules (I2S and I3S) or situations in between (I-I-S).

Cinematographic study of stochastic chemical events at atomic resolution.

The advent of single-molecule atomic-resolution time-resolved electron microscopy (SMART-EM) has created a new field of 'cinematic chemistry,' allowing for the cinematographic recording of dynamic behaviors of organic and inorganic molecules and their assembly. However, the limited electron dose per frame of video images presents a major challenge in SMART-EM. Recent advances in direct electron counting cameras and techniques to enhance image quality through the implementation of a denoising algorithm have enabled the tracking of stochastic molecular motions and chemical reactions with sub-millisecond temporal resolution and sub-angstrom localization precision. This review showcases the development of dynamic molecular imaging using the SMART-EM technique, highlighting insights into nanomechanical behavior during molecular shuttle motion, pathways of multistep chemical reactions, and elucidation of crystallization processes at the atomic level.

Thermal annealing promoted room temperature phosphorescence: motion models and internal mechanism.

Thermal annealing has been proven to be an efficient method to optimize the device performance of organic and polymeric opto-electronic materials. However, no detailed information of aggregate structures was obtained for a deeper understanding of what happens during thermal annealing. Herein, through modulation of molecular configurations by tunable linkage positions, and the amplified amplitudes of molecular motions by incorporation of additional methylene units, accurate changes of aggregated structures upon thermal annealing have been achieved, accompanying with the 'turn-on' room temperature phosphorescence (RTP) response by about 4800- and 177-fold increase of lifetimes. The stretching and swing motion models have been proposed, which afforded an efficient way to investigate the science of dynamic aggregation in depth.

A generative model to simulate spatiotemporal dynamics of biomolecules in cells.

Generators of space-time dynamics in bioimaging have become essential to build ground truth datasets for image processing algorithm evaluation such as biomolecule detectors and trackers, as well as to generate training datasets for deep learning algorithms. In this contribution, we leverage a stochastic model, called birth-death-move (BDM) point process, in order to generate joint dynamics of biomolecules in cells. This particle-based stochastic simulation method is very flexible and can be seen as a generalization of well-established standard particle-based generators. In comparison, our approach allows us: (1) to model a system of particles in motion, possibly in interaction, that can each possibly switch from a motion regime (e.g., Brownian) to another (e.g., a directed motion); (2) to take into account finely the appearance over time of new trajectories and their disappearance, these events possibly depending on the cell regions but also on the current spatial configuration of all existing particles. This flexibility enables to generate more realistic dynamics than standard particle-based simulation procedures, by for example accounting for the colocalization phenomena often observed between intracellular vesicles. We explain how to specify all characteristics of a BDM model, with many practical examples that are relevant for bioimaging applications. As an illustration, based on real fluorescence microscopy datasets, we finally calibrate our model to mimic the joint dynamics of Langerin and Rab11 proteins near the plasma membrane, including the well-known colocalization occurrence between these two types of vesicles. We show that the resulting synthetic sequences exhibit comparable features as those observed in real microscopy image sequences.

Directional and inter-acquisition variability in diffusion-weighted imaging and editing for restricted diffusion.

PURPOSE: To evaluate and quantify inter-directional and inter-acquisition variation in diffusion-weighted imaging (DWI) and emphasize signals that report restricted diffusion to enhance cancer conspicuity, while reducing the effects of local microscopic motion and magnetic field fluctuations. METHODS: Ten patients with biopsy-proven prostate cancer were studied under an Institutional Review Board-approved protocol. Individual acquisitions of DWI signal intensities were reconstructed to calculate inter-acquisition distributions and their statistics, which were compared for healthy versus cancer tissue. A method was proposed to detect and filter the acquisitions affected by motion-induced signal loss. First, signals that reflect restricted diffusion were separated from the acquisitions that suffer from signal loss, likely due to microscopic motion, by imposing a cutoff value. Furthermore, corrected apparent diffusion coefficient maps were calculated by employing a weighted sum of the multiple acquisitions, instead of conventional averaging. These weights were calculated by applying a soft-max function to the set of acquisitions per-voxel, making the analysis immune to acquisitions with significant signal loss, even if the number of such acquisitions is high. RESULTS: Inter-acquisition variation is much larger than the Rician noise variance, local spatial variations, and the estimates of diffusion anisotropy based on the current data, as well as the published values of anisotropy. The proposed method increases the contrast for cancers and yields a sensitivity of 98 . 8 % $$ 98.8\% $$ with a false positive rate of 3 . 9 % $$ 3.9\% $$ . CONCLUSION: Motion-induced signal loss makes conventional signal-averaging suboptimal and can obscure signals from areas with restricted diffusion. Filtering or weighting individual acquisitions prior to image analysis can overcome this problem.

Structural phase transition in a charge-transfer compound: tropylium hexafluoridoantimonate(V)-1,4-dimethylnaphthalene (1/1).

Molecular motion in crystals has attracted much attention for the development of stimuli-responsive materials. The most studied are molecules with few atoms or highly symmetrical molecules. To develop molecules with new motion characteristics, we synthesized a charge-transfer compound, namely, tropylium hexafluoridoantimonate(V)-1,4-dimethylnaphthalene (1/1), (C7H7)[SbF6]·C12H12, and studied its structural phase transition. In this compound, the tropylium cation and the 1,4-dimethylnaphthalene molecule have planar geometry, but the latter has low symmetry. They are stacked as a one-dimensional chain structure through π-π charge-transfer interactions. Weak intermolecular interactions and planar molecular geometry result in a large degree of freedom of in-plane motion. Upon heating, due to the in-plane rotation of the molecules, the compound undergoes an order-disorder structural phase transition (phase-transition temperature = 334 K). The space group of the room-temperature phase is P21/m and the space group of the high-temperature phase is P4/mmm. This phase transition is accompanied by significant dielectric anomalies. The current investigation shows that the structural features of the title compound can be used to construct functional materials with phase transitions, such as molecular ferroelectrics.

Molecular Motion and Nonradiative Decay: Towards Efficient Photothermal and Photoacoustic Systems.

Nonradiative decay invariably competes with radiative decay during the deexcitation process of matter. In the community of luminescence research, nonradiative decay has been deemed less attractive than radiative decay. However, all things in their being are good for something and so is nonradiative decay. As the molecular motion-facilitated nonradiative decay (MMFND) effect is inevitable in photophysical processes, it provides a new avenue to convert the harvested light energy into exploitable forms by harnessing molecular motion. In many cases, active molecular motion enables thermal deactivation from excited states. In this Minireview, recent advances in photothermal and photoacoustic systems with MMFND character are summarized. We believe that this presentation of the rational engineering of molecular motion for efficient photothermal generation will deepen the understanding of the relationship between molecular motion and nonradiative decay and navigate people to rethink the positive aspects of nonradiative decay for the establishment of new light-controllable techniques.

Oxygen Quenching-Resistant Nanoaggregates with Aggregation-Induced Delayed Fluorescence for Time-Resolved Mapping of Intracellular Microviscosity.

Microviscosity is a fundamental parameter in the biophysics of life science and governs numerous cellular processes. Thus, the development of real-time quantitative monitoring of microviscosity inside cells is important. The traditional probes for detecting microviscosity via time-resolved luminescence imaging (TRLI) are generally disturbed by autofluorescence or surrounding oxygen in cells. Herein, we developed loose packing nanoaggregates with aggregation-induced delayed fluorescence (FKP-POA and FKP-PTA) and free from the effect of oxygen and autofluorescence for viscosity mapping via TRLI. The feasibility of FKP-PTA nanoparticles (NPs) for microviscosity mapping through TRLI was demonstrated by monitoring the variation of microviscosity inside HepG2 cancer cells, which demonstrated a value change from 14.9 cP to 216.9 cP during the apoptosis. This indicates that FKP-PTA NP can be used as a probe for cellular microviscosity mapping to help people to understand the physiologically dynamic microenvironment. The present results are expected to promote the advancement of diagnostic and therapeutic methods to cope with related diseases.

Topochemical Postulates: Are They Relevant for Topochemical Reactions Occurring at Elevated Temperatures?

A rigid inositol-derived monomer functionalized with azide and alkyne as the complementary reactive groups (CRGs) crystallized as three distinct polymorphs I-III. Despite the unsuitable orientation of CRGs in the crystals for complete polymerization, all the three polymorphs underwent regiospecific and quantitative topochemical azide-alkyne cycloaddition (TAAC) polymerization upon heating to yield three different polymorphs of 1,2,3-triazol-1,4-diyl-linked-poly-neo-inositol. The molecules in these polymorphs exploit the weak intermolecular interactions, free space in the crystal lattice, and heat energy for their large and cooperative molecular motion to attain a transient reactive orientation, ultimately leading to the regiospecific TAAC reaction yielding distinct crystalline polymers. This study cautions that the overreliance on topochemical postulates for the prediction of topochemical reactivity at high temperatures could be misleading.

Novel Quinolizine AIE System: Visualization of Molecular Motion and Elaborate Tailoring for Biological Application.

Molecular motions are ubiquitous in nature and they immutably play intrinsic roles in all actions. However, exploring appropriate models to decipher molecular motions is an extremely important but very challenging task for researchers. Considering aggregation-induced emission (AIE) luminogens possess their unique merits to visualize molecular motions, it is particularly fascinating to construct new AIE systems as models to study molecular motion. Herein, a novel quinolizine (QLZ) AIE system was constructed based on the restriction intramolecular vibration (RIV) mechanism. It was demonstrated that QLZ could act as an ideal model to visualize single-molecule motion and macroscopic molecular motion via fluorescence change. Additionally, further elaborate tailoring of this impressive core achieved highly efficient reactive oxygen species production and realized fluorescence imaging-guided photodynamic therapy applications, which confirms the great application potential of this new AIE-active QLZ core. Therefore, this work not only provides an ideal model to visualize molecular motion but also opens a new way for the application of AIEgens.

Solid-state intramolecular motions in continuous fibers driven by ambient humidity for fluorescent sensors.

One striking feature of molecular rotors is their ability to change conformation with detectable optical signals through molecular motion when stimulated. However, due to the strong intermolecular interactions, synthetic molecular rotors have often relied on fluid environments. Here, we take advantage of the solid-state intramolecular motion of aggregation-induced emission (AIE) molecular rotors and one-dimensional fibers, developing highly sensitive optical fiber sensors that respond to ambient humidity rapidly and reversibly with observable chromatic fluorescence change. Moisture environments induce the swelling of the polymer fibers, activating intramolecular motions of AIE molecules to result in red-shifted fluorescence and linear response to ambient humidity. In this case, polymer fiber provides a process-friendly architecture and a physically tunable medium for the embedded AIE molecules to manipulate their fluorescence response characteristics. Assembly of sensor fibers could be built into hierarchical structures, which are adaptive to diverse-configuration for spatial-temporal humidity mapping, and suitable for device integration to build light-emitting sensors as well as touchless positioning interfaces for intelligence systems.

Insights Into the Micelle-Induced ß-Hairpin-to-α-Helix Transition of a LytA-Derived Peptide by Photo-CIDNP Spectroscopy.

A choline-binding module from pneumococcal LytA autolysin, LytA239-252, was reported to have a highly stable nativelike ß-hairpin in aqueous solution, which turns into a stable amphipathic α-helix in the presence of micelles. Here, we aim to obtain insights into this DPC-micelle triggered ß-hairpin-to-α-helix conformational transition using photo-CIDNP NMR experiments. Our results illustrate the dependency between photo-CIDNP phenomena and the light intensity in the sample volume, showing that the use of smaller-diameter (2.5 mm) NMR tubes instead of the conventional 5 mm ones enables more efficient illumination for our laser-diode light setup. Photo-CIDNP experiments reveal different solvent accessibility for the two tyrosine residues, Y249 and Y250, the latter being less accessible to the solvent. The cross-polarization effects of these two tyrosine residues of LytA239-252 allow for deeper insights and evidence their different behavior, showing that the Y250 aromatic side chain is involved in a stronger interaction with DPC micelles than Y249 is. These results can be interpreted in terms of the DPC micelle disrupting the aromatic stacking between W241 and Y250 present in the nativelike ß-hairpin, hence initiating conversion towards the α-helix structure. Our photo-CIDNP methodology represents a powerful tool for observing residue-level information in switch peptides that is difficult to obtain by other spectroscopic techniques.