Flexible Molecules Research Articles

Enhanced Sampling Simulations of RNA-Peptide Binding Using Deep Learning Collective Variables.

Enhanced sampling (ES) simulations of biomolecular recognition, such as binding small molecules to proteins and nucleic acid targets, protein-protein association, and protein-nucleic acid interactions, have gained significant attention in the simulation community because of their ability to sample long-time scale processes. However, a key challenge in implementing collective variable (CV)-based enhanced sampling methods is the selection of appropriate CVs that can distinguish the system's metastable states and, when biased, can effectively sample these states. This challenge is particularly acute when the binding of a flexible molecule to a conformationally rich host molecule is simulated, such as the binding of a peptide to an RNA. In such cases, a large number of CVs are required to capture the conformations of both the host and the guest as well as the binding process. Using such a large number of descriptors is impractical in any enhanced sampling simulation method. In our work, we used the recently developed deep targeted discriminant analysis (Deep-TDA) method to design CVs to study the binding of a cyclic peptide, L22, to a TAR RNA of HIV, which is a prototypical system. The Deep-TDA CV, obtained from a nonlinear combination of important contact pairs between the L22 peptide and the host RNA backbone atoms, along with the RNA apical loop RMSD as the second CV were used in the on-the-fly probability-based enhanced sampling (OPES) simulation to sample the reversible binding and unbinding of the L22 peptide to the TAR RNA target. The OPES simulation delineated the mechanism of peptide binding and unbinding to and from the RNA and enabled the calculation of the underlying free energy landscape. Our results demonstrate the potential of the Deep-TDA method for designing CVs to study complex biomolecular recognition processes.

Flexible molecules dedicate to release strain of inverted inorganic perovskite solar cell

The tensile strain in inorganic perovskite films induced by thermal annealing is one of the primary factors contributing to the inefficiency and instability of inorganic perovskite solar cells (IPSCs), which reduces the defect formation energy. Here, a flexible molecule 5-maleimidovaleric acid (5-MVA) was introduced as a strain buffer to release the residual strain of CsPbI2.85Br0.15 perovskite. Maleic anhydride and carboxyl groups in 5-MVA interact strongly with the uncoordinated Pb2+ through Lewis acid-base reaction, thus tightly “pull” the perovskite lattice. The in-between soft carbon chain increased the structural flexibility of CsPbI2.85Br0.15 perovskite materials, which effectively relieved the intrinsic internal strain of CsPbI2.85Br0.15, resisted the corrosion of external strain, and also reduced the formation of defects such as VI and Pb0. In addition, the introduction of 5-MVA improved crystal quality, passivated residual defects, and narrowed energy level barriers. Eventually, power conversion efficiency (PCE) of NiOx-based inverted IPSCs increased from 19.25% to 20.82% with the open-circuit voltage enhanced from 1.164 V to 1.230 V. The release of strain also improved the stability of CsPbI2.85Br0.15 perovskite films and devices.

Determining structures of RNA conformers using AFM and deep neural networks.

Much of the human genome is transcribed into RNAs1, many of which contain structural elements that are important for their function. Such RNA molecules-including those that are structured and well-folded2-are conformationally heterogeneous and flexible, which is a prerequisite for function3,4, but this limits the applicability of methods such as NMR, crystallography and cryo-electron microscopy for structure elucidation. Moreover, owing to the lack of a large RNA structure database, and no clear correlation between sequence and structure, approaches such as AlphaFold5 for protein structure prediction do not apply to RNA. Therefore, determining the structures of heterogeneous RNAs remains an unmet challenge. Here we report holistic RNA structure determination method using atomic force microscopy, unsupervised machine learning and deep neural networks (HORNET), a novel method for determining three-dimensional topological structures of RNA using atomic force microscopy images of individual molecules in solution. Owing to the high signal-to-noise ratio of atomic force microscopy, this method is ideal for capturing structures of large RNA molecules in distinct conformations. In addition to six benchmark cases, we demonstrate the utility of HORNET by determining multiple heterogeneous structures of RNase P RNA and the HIV-1 Rev response element (RRE) RNA. Thus, our method addresses one of the major challenges in determining heterogeneous structures of large and flexible RNA molecules, and contributes to the fundamental understanding of RNA structural biology.

When can flexible weak polyelectrolytes be treated as effective rigid objects?

Conformational and ionization equilibria of flexible weak polyelectrolytes (PEs) are, in general, strongly coupled. In this article, we analyze the effect of averaging over (or "contracting") the conformational degrees of freedom so that the original flexible molecule is replaced by an effective rigid object with the same ionization properties. As a result, one obtains the so-called Site Binding (SB) model, much easier to treat both theoretically and computationally, and extensively used to characterize the ionization properties of PE. The conformational averages can be performed in a systematic way by means of the Conformational Contraction Equations (CCEs), which relate the SB parameters to the underlying conformational equilibrium. The conditions for the convergence of the CCE are evaluated in the presence of both Short Range (SR) and Long Range (LR) electrostatic interactions. Two analytically solvable models based on the Freely Jointed Chain (FJC), involving only SR interactions, are analyzed at first. Despite the large chain flexibility, the resulting SB model reproduces the ionization properties with high accuracy. In the case of independent bonds, a very flexible chain can be exactly replaced by an effective rigid object with neighboring pairwise interactions. In general, however, triplet and higher order interactions emerge at the SB level. When LR electrostatic interactions are introduced and combined with the FJC large chain flexibility, the convergence of the CCE for long chains becomes problematic since the SB free energy must be truncated. Similar conclusions are reached for the freely rotating chain and rotational isomeric state models.

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 the PES has bond angle (H-S-H) of 92.40° and bond length (S-H) of 1.338 Å. The PES shows that hydrogen sulfide is a quite flexible molecule. Namely, it can change the bonding angle (H-S-H) in the range of 15.6° (from 84.6° to 100.2°) 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.

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 hexagonal 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 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

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