Flexible Molecules Research Articles

To Gibbs or Not to Gibbs Effect of Entropic Contribution in the NMR Calculations of Flexible and Polar Molecules-Updating the DP4+App.

The application of quantum-based NMR methods for the structural elucidation of natural and unnatural products has grown significantly. However, accurately calculating the conformational landscape of flexible molecules with intricate intramolecular hydrogen bonding (IHB) networks continues to be a major challenge. In this work, we thoroughly studied the effect of entropic contributions (trough Gibbs free energies calculations) in the DP4+ performance. Our results show that to solve biased systems with strong IHB interactions requires computing the Boltzmann contributions using Gibbs free energies computed with at least triple-ξ basis set and SMD solvation model. In response to this finding, we have updated our DP4+App, a user-friendly Python applet that automates the entire process of calculating DP4+ probabilities. In the new version, the program allows for calculating of conformational contributions at any selected theory level, using either SCF or Gibbs free energies.

How the Spacer Influences the Stability of 2D Perovskites?

Two-dimensionallead halide perovskites (2D HPs) represent as an emerging class of materials given their tunable optoelectronic properties and long-term stability in perovskite solar cells. However, the ever-growing field of optoelectronic devices using 2D HPs requires fundamental understanding of the influence of the spacer on the physiochemical properties and stability of perovskites as well as establish which cation properties are closely related to suppress the halogen ion mobility. This study focuses on investigating the influence of organic spacers with intrinsic properties (e.g., rigidity and flexibility, special groups) and variations of material dimensions on the stability of halogen ions and inorganic frameworks in 2D HPs. It is found that the perovskite structure composed of rigidity molecules owns better stability of halogen ion and inorganic framework than that of flexible molecules. The stability of ions exhibits a negative correlation with the dimensions of perovskite. More importantly, a simple descriptor for measuring the stability of halogen ions in 2D HPs is constructed. By causal discovery algorithms with more physical and chemical significance, the Kappa shape index, number of rotatable bonds, and aromatic carbocycles in organic spacers are identified as causal and important features for the stability of halogen ions in 2D HPs.

Layer-by-layer assembling boron nitride/polyethyleneimine/MXene hierarchical sandwich structure onto basalt fibers for high-performance epoxy composites

Interfacial adhesion directly affects the mechanical properties of basalt fiber (BF)-reinforced polymer composites. To construct a more superior interphase between BFs and epoxy resin (EP) than a weak interphase of the unmodified BF/EP, we propose a hierarchical sandwich structure consisting of sodium hydroxide–activated boron nitride (BNOH), polyethyleneimine (PEI), and MXene (MX, Ti3C2Tx) through facile layer-by-layer self-assembly. The fabricated BNOH/P/MX sandwich structure (P denoting “PEI”) can synergistically improve the interface adhesion by enhancing the mechanical interlocking and chemical bonding of the composites. When the composites reinforced by BF–BNOH/P/MX subject to the external loading, flexible PEI molecules allow two-dimensional (2D) rigid BNOH and MX nanosheets to slip at the interface by uncurling the molecular chains, dissipating a great amount of energy during the fracture progress. Meanwhile, the hierarchical BNOH/P/MX sandwich structure acts as an excellent interface and possesses multistage gradient modulus and wider thickness, uniformly and efficiently transferring the stress from the EP matrix to BFs. The interfacial shear strength, impact strength, and fracture toughness of BF–BNOH/P/MX-reinforced EP composite are substantially improved by 45.9 %, 60.6 %, and 148.9 %, respectively, compared with bare BF–based composites. This study can provide valuable references and inspirations for designing and constructing high-quality interfaces for high-strength and high-toughness BF structural materials, taking advantage of 2D materials.

Phase change thermal interface film with bicontinuous and textured filler network for efficient wearable heat dissipation

Wearable thermal management needs to simultaneously meet thermal conductivity, heat storage capacity, stability, flexibility, and economy, but these characteristics constrain each other in the development of phase change thermal interface materials (PhC-TIM). Therefore, relying on the economic bicontinuous structure for fillers’ orientation, a new type of bicontinuous phase change thermal interface material (BPTIM) was designed, which includes thermal storage phase composed of paraffin (PCMs) and flexible molecule styrene–butadiene–styrene (SBS), and thermal conductivity phase composed of adhesive polyurethane (PU) and thermal conductive medium boron nitride (h-BN). In the experiment, shear force generated by stirring and optimized two-phase volume ratio resulted in the stretching and compressing of the thermal conductive phase, promoting the orientation of h-BN and ultimately forming a textured thermal-conductive network in a high PCMs content bicontinuous structure. Moreover, the introduction of SBS had brought bending resistance and thermal stability. These characteristics enabled BPTIMs to significantly reduce the surface temperature of the wearable device by 23 °C. Overall, this design provides a certain reference for the widespread application of PhC-TIM in thermal management of wearable electronic products.

Discovery and Selective Nucleation of Polymorphs of Flexible GABA Molecules: Solvation Effects and Conformational Rearrangement

Discovery and Selective Nucleation of Polymorphs of Flexible GABA Molecules: Solvation Effects and Conformational Rearrangement

How Flexible Is the Hydrogen Sulfide Molecule Structure? Influence of Hydrogen Sulfide Molecule Geometry on Its Hydrogen Bonds.

The geometry of hydrogen sulfide was studied by calculating potential energy surface (PES) with over 1800 configurations. The calculations were performed at very accurate CCSD(T)/aug‐cc‐pvz5 level. The most stable geometry on PES has bond angle (H‐S‐H) of 92.40⁰ and bond length (S‐H) of 1.338 Å. PES shows that hydrogen sulfide is a quite flexible molecule. Namely, it can change the bonding angle (H‐S‐H) in the range of . 15.6⁰ (from 84.6⁰ to 100.2⁰) and the bond lengths (S‐H) in the range of 0.082 Å (from 1.299 Å to 1.381 Å) with an energy increase of only 1.0 kcal/mol. An influence of hydrogen sulfide geometry on its hydrogen bonds was studied on several hydrogen sulfide/hydrogen sulfide and water/hydrogen sulfide dimers. It showed that the change of hydrogen sulfide geometry does not influence the strength of hydrogen bond. Fully optimized geometries in gas and water solution phases revealed structural differences of both monomers and dimers in gas phase and water phase. SAPT analysis of the optimized dimer geometries showed that in all the dimers electrostatic is the most dominant contribution, while, in the dimers with hydrogen sulfide, the influence of dispersion contribution becomes quite pronounced.

Ultrahigh Subcooling Dropwise Condensation Heat Transfer on Slippery Liquid-like Monolayer Grafted Surfaces.

Rapid and continuous droplet shedding is crucial for many applications, including thermal management, water harvesting, and microfluidics, among others. Superhydrophobic surfaces, though effective, suffer from droplet pinning at high subcooling temperature (Tsub). Conversely, slippery liquid-like surfaces covalently bonded with flexible hydrophobic molecules show high stability and low droplet adhesion attributed to their dense and ultrasmooth water repellent polymer chains, enhancing dropwise condensation and rapid shedding. In this work, linear poly(dimethylsiloxane) chains of various viscosities are covalently bonded onto silicon substrates to form thin and smooth monolayer coated surfaces. The formation of the monolayer is characterized by cryogenic transmission electron microscopy. On these surfaces a very low contact angle hysteresis is reported within wide surface temperature ranges as well as continuous dropwise condensation at ultrahigh Tsub of 60 K. In particular, one of the highest condensation heat fluxes of 1392.60 kW·m-2 and a heat transfer coefficient of 23.21 kW·m-2·K-1 at ultrahigh Tsub of 60 K is reported. The experimental heat transfer performance is further compared to the theoretical heat transfer via the individual droplets with the droplet distribution elucidated via both macroscopic observations as well as environmental scanning electron microscopy. Finally, only a mild decrease in the heat transfer coefficient of 20.3% after 100 h of condensation test at Tsub of 60 K is reported. Slippery liquid-like surfaces promote droplet shedding and sustain dropwise condensation at high Tsub without flooding empowered by the lower frictional forces, addressing challenges in heat transfer performance and durability.

Angular-Inertia Regulated Stable and Nanoscale Sensing of Single Molecules Using Nanopore-In-A-Tube.

Nanopore is commonly used for high-resolution, label-free sensing, and analysis of single molecules. However, controlling the speed and trajectory of molecular translocation in nanopores remains challenging, hampering sensing accuracy. Here, the study proposes a nanopore-in-a-tube (NIAT) device that enables decoupling of the current signal detection from molecular translocation and provides precise angular inertia-kinetic translocation of single molecules through a nanopore, thus ensuring stable signal readout with high signal-to-noise ratio (SNR). Specifically, the funnel-shaped silicon nanopore, fabricated at a 10-nm resolution, is placed into a centrifugal tube. A light-induced photovoltaic effect is utilized to achieve a counter-balanced state of electrokinetic effects in the nanopore. By controlling the inertial angle and centrifugation speed, the angular inertial force is harnessed effectively for regulating the translocation process with high precision. Consequently, the speed and trajectory of the molecules are able to be adjusted in and around the nanopore, enabling controllable and high SNR current signals. Numerical simulation reveals the decisive role of inertial angle in achieving uniform translocation trajectories and enhancing analyte-nanopore interactions. The performance of the device is validated by discriminating rigid Au nanoparticles with a 1.6-nm size difference and differentiating a 1.3-nm size difference and subtle stiffness variations in flexible polyethylene glycol molecules.

Templated Nucleation of Clotrimazole and Ketoprofen on Polymer Substrates.

The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API-polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API-polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API-polymer interaction energies are correlated with heterogeneous crystallization outcomes.

Comparative Molecular Dynamics Simulation of Wetting on Liquid-like Surfaces.

We utilize molecular dynamics simulations to comparably investigate the wetting and motion behavior of droplets on liquid-like surfaces (LLS) with varying grafting conditions. Polydimethylsiloxane (PDMS) and perfluoropolyether (PFPE) have been considered to be flexible molecules versus rigid molecules of trichloro(octadecyl) silane (OTS) and trichloro(1H,1H,2H,2H-perfluorooctyl) silane (PFOS), respectively. Our findings reveal that droplets on surfaces tethered with either PDMS or PFPE brushes can generate indentations and wetting ridges, providing microscopic evidence of their liquid-like nature. The grafting density of mobile chains exerts a dominant influence on the wetting properties compared to the molecular weight. A parameter map is created to pinpoint the precise range of grafting densities essential for the optimal construction of LLS at predetermined molecular weights. Furthermore, the investigation of droplet motion dynamics on LLS demonstrates that droplets consistently exhibit a rolling state, regardless of the intensity of the applied lateral force. The movement pattern of the droplet shifts only under conditions where the grafting density is significantly reduced and the substrate exhibits hydrophilic tendencies. These findings and the developed model are anticipated to offer valuable guidelines for optimal designs of LLS.

Molecular structure refinement based on residual dipolar couplings using magnetic-field rotational sampling.

A method for structure refinement of molecules based on residual dipolar coupling (RDC) data is proposed. It calculates RDC values using magnetic-field rotational sampling of the rotational degrees of freedom of a molecule in conjunction with molecule-internal configurational sampling. By applying rotational sampling, as is occurring in the experiment, leading to observable RDCs, the method stays close to the experiment. It avoids the use of an alignment tensor and, therefore, the assumptions that the overall rotation of the molecule is decoupled from its internal motions and that the molecule is rigid. Two simple molecules, a relatively rigid and a very flexible cyclo-octane molecule with eight aliphatic side chains containing 24 united atoms, serve as so-called "toy model" test systems. The method demonstrates the influence of molecular flexibility, force-field dominance, and the number of RDC restraints available on the outcome of structure refinement based on RDCs. Magnetic-field rotational sampling is basically equivalent but more efficient than explicitly sampling the rotational degrees of freedom of the molecule. In addition, the performance of the method is less dependent on the number NRDC of measured RDC-values available. The restraining forces bias the overall orientation distribution of the molecule correctly. This study suggests that the information content of RDCs with respect to molecular structure is limited.

Molecular Dynamics‐Based Conformational Simulation Method for Analysis of Arrival Time Distributions in Ion Mobility Mass Spectrometry

AbstractIon mobility‐mass spectrometry (IM‐MS) has recently contributed to the structural analysis of molecules, including supramolecules and proteins, by determining the ion arrival time distributions correlated with the collision cross sections (CCSs), as well as the mass‐to‐charge ratios. However, its application range is still limited owing to the lack of general CCSs simulation methods based on possible molecular conformations. Here, a molecular dynamics‐based conformational search method for simulating CCS distributions using projection approximation is reported. As a case study, the gas‐phase conformations of the sodium adducts of conformationally flexible polyketones with 3,3‐dimethylpentane‐2,4‐dione as the monomer are analyzed. The sodium adduct of the hexamer (m/z 781.4 for [1 + Na]+) showed a monomodal arrival time distribution, but that of the octamer sodium adduct (m/z 1033.5 for [2 + Na]+) is multimodal. The conformational analysis indicated an unimodal CCS distribution of simulated [1 + Na]+ conformations in which the sodium cation is mainly bound at the chain terminal. Conversely, four clusters of conformations are obtained for [2 + Na]+ based on the Na+‐coordination sites, which qualitatively reproduced the observed CCS distribution. This approach will extend the utility of IM‐MS for the conformational analysis of flexible molecules in the gas phase.

Multipocket Cage Enables the Binding of High-Order Bulky and Drug Guests Uncovered by MS Methodology.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

In vivo turnover and biodistribution of soluble AXL: implications for biomarker development

Soluble biomarkers are paramount to personalized medicine. However, the in vivo turnover and biodistribution of soluble proteins is seldom characterized. The cleaved extracellular domain of the AXL receptor (sAXL) is a prognostic biomarker in several diseases and a predictive marker of AXL targeting agents. Plasma sAXL reflects a balance between production in tissues with lymphatic transport into the circulation and removal from blood by degradation or excretion. It is unclear how this transport cycle affects plasma sAXL levels that are the metric for biomarker development. Radiolabeled mouse sAxl was monitored after intravenous injection to measure degradation and urinary excretion of sAxl, and after intradermal injection to mimic tissue or tumor production. sAxl was rapidly taken-up and degraded by the liver and kidney cortex. Surprisingly, intact sAxl was detectable in urine, indicating passage through the glomerular filter and a unique sampling opportunity. The structure of sAxl showed an elongated, flexible molecule with a length of 18 nm and a thickness of only 3 nm, allowing passage through the glomerulus and excretion into the urine. Intradermally injected sAxl passed through local and distant lymph nodes, followed by uptake in liver and kidney cortex. Low levels of sAxl were seen in the plasma, consistent with an extended transit time from local tissue to circulation. The rapid plasma clearance of sAxl suggests that steady-state levels in blood will sensitively and dynamically reflect the rate of production of sAxl in the tissues but will be influenced by perturbations of liver and kidney function.

Single-Molecule Identification of the Isomers of a Lipidic Antibody Activator.

Molecular structural elucidation can be accomplished by different techniques, such as nuclear magnetic resonance or X-ray diffraction. However, the former does not give information about the three-dimensional atomic arrangement, and the latter needs crystallizable solid samples. An alternative is direct, real-space visualization of the molecules by cryogenic scanning tunneling microscopy (STM). This technique is usually limited to thermally robust molecules because an annealing step is required for sample deposition. A landmark development has been the coupling of STM with electrospray deposition (ESD), which smooths the process and widens the scope of the visualization technique. In this work, we present the on-surface characterization of air-, light-, and temperature-sensitive rhamnopolyene with relevance in molecular biology. Supported by theoretical calculations, we characterize two isomers of this flexible molecule, confirming the potential of the technique to inspect labile, non-crystallizable compounds.

Hamiltonian Cycles on Ammann-Beenker Tilings

We provide a simple algorithm for constructing Hamiltonian graph cycles (visiting every vertex exactly once) on a set of arbitrarily large finite subgraphs of aperiodic two-dimensional Ammann-Beenker (AB) tilings. Using this result, and the discrete scale symmetry of AB tilings, we find exact solutions to a range of other problems which lie in the complexity class NP-complete for general graphs. These include the equal-weight traveling salesperson problem, providing, for example, the most efficient route a scanning tunneling microscope tip could take to image the atoms of physical quasicrystals with AB symmetries; the longest path problem, whose solution demonstrates that collections of flexible molecules of any length can adsorb onto AB quasicrystal surfaces at density one, with possible applications to catalysis; and the three-coloring problem, giving ground states for the q-state Potts model (q≥3) of magnetic interactions defined on the planar dual to AB, which may provide useful models for protein folding. Published by the American Physical Society 2024

High resolution far-infrared synchrotron spectroscopy of 2-furfural conformers: Fundamental and hot bands.

In the continuity of a previous jet-cooled rovibrational study of trans and cis conformers of 2-furfural in the mid-infrared region (700-1750cm-1) [Chawananon et al., Molecules 28 (10), 4165 (2023)], the present work investigates the far-infrared spectroscopy of 2-furfural using a long path absorption cell coupled to a high-resolution Fourier transform spectrometer and synchrotron radiation at the AILES beamline of the SOLEIL synchrotron. Guided by anharmonic calculations, vibrational energy levels and excited-state rotational constants are sufficiently predictive for a complete assignment of all fundamental and combination bands up to 700cm-1, as well as the rovibrational analysis of 4 (1) low-frequency modes of trans-(cis-)2-furfural. A global rovibrational simulation, including far-infrared rovibrational lines and microwave and millimeter-wave rotational lines assigned in a previous study [Motiyenko et al., J. Mol. Spectrosc., 244, 9 (2007)] provides a reliable set of ground- and excited-state rotational parameters involving ring torsion, bending, and ring puckering modes of 2-furfural. In a second step, a rovibrational analysis of several hot band sequences, mainly involving the lowest frequency ring CHO torsion mode, is carried out. Reliable values of some anharmonic coefficients are obtained experimentally and could serve as a benchmark for validating advanced anharmonic calculations related to these large amplitude motions of flexible molecules.

Synthesis, solid-state structures, and properties of linear and tripodal flexible molecules with pyrazinopyrazine moieties

Abstract Pyrazino[2,3-b]pyrazine, which is a naphthalene analog with iminium nitrogen atoms at 1,4,5,8-positions instead of sp2-carbon atoms, is attractive as a building block for nitrogen highly contained π-conjugated systems. In this study, we synthesized pyrazino[2,3-b]pyrazine-based linear and tripodal molecules, in which pyrazino[2,3-b]pyrazine moieties are bonded with the central benzene ring at 1,4-positions and 1,3,5-positions, respectively, giving conformationally flexible and moderately π-conjugated molecules. It is noteworthy that the tripodal one forms unique interdigitated dimer with a small cavity in a crystalline state because of flexible tripodal molecular shape.

A variant on the CREST iMTD algorithm for noncovalent clusters of flexible molecules.

Conformational ensemble generation and the search for the global minimum conformation are important problems in computational chemistry. In this work, a variant on the conformer-rotamer ensemble sampling tool (CREST) iterative metadynamics (iMTD) algorithm designed for determining structural ensembles and energetics of noncovalent clusters of flexible molecules is presented. We term this new algorithm a low-energy diversity-enhanced variant on CREST, or LEDE-CREST. As with CREST, the energies are evaluated using the semiempirical GFN2-xTB extended tight binding approach. The utility of the algorithm is highlighted by generating ensembles for a variety of noncovalent clusters of flexible or rigid monomers using both CREST and LEDE-CREST.

Adaptive Reaktion bei der Lösung von flexiblen Molekülen: Oligohydrate von 4‐Hydroxy‐2‐butanon

AbstractDurch Wasser hervorgerufene Strukturveränderungen spielen eine zentrale Rolle in der Chemie und Biologie, sind aber auf molekularer Ebene nach wie vor schwer vorherzusagen, zu messen und zu kontrollieren. Hier untersuchen wir in der Gasphase die größenabhängige Wasseraggregation am flexiblen Molekül 4‐Hydroxy‐2‐butanon und modellieren die Konformationsanpassungsfähigkeit flexibler Substrate an Wirtswassergerüste, sowie die Präferenzen für sequentielles Tröpfchenwachstum. Das Experiment wurde mittels breitbandiger Rotationsspektroskopie durchgeführt und mit quantenchemischen Berechnungen nachvollzogen. Experimentell wurden vom Di‐ bis zum Pentahydrat (4‐Hydroxy‐2‐butanon‐(H2O)n=2–5) zwei verschiedene Isomere beobachtet, einschließlich der 18O‐Isotopologen für die Di‐ und Trihydrate. Um Wassermoleküle effektiv unterzubringen, verändert sich interessanterweise das schwere Atomgerüst von 4‐Hydroxy‐2‐butanon in jedem beobachteten Isomer und entspricht nicht der stabilen Konformation des freien Monomers. Alle Solvate gehen von der Alkoholgruppe (Protonendonor) aus, behalten aber die Carbonylgruppe als sekundären Bindungspunkt bei. Die Wassergerüste ähneln stark denen in reinen Wasserclustern und balancieren zwischen der Fähigkeit von 4‐Hydroxy‐2‐butanon, die Orientierung und Position der Wassermoleküle zu steuern, und der Fähigkeit von Wasser, die Konformation des Monomers zu modulieren. Die vorliegende Arbeit liefert somit eine genaue molekulare Beschreibung, wie sich torsionsflexible Moleküle im Verlauf der fortschreitenden Solvatation dynamisch an Wasser anpassen.