Molecular Systems Design & Engineering最新文献

Glucose-responsive hydrogel systems are increasingly explored for insulin delivery, with dynamic-covalent crosslinking interactions between phenylboronic acids (PBA) and diols forming a key glucose-sensing mechanism. However, commonly used PBA and diol chemistries often have limited responsiveness to glucose under physiological concentrations. This is due, in part, to the binding of PBA to the commonly used diol chemistries having higher affinity than for PBA to glucose. The present study addresses this challenge by redesigning the diol chemistry in an effort to reduce its binding affinity to PBA, thereby enhancing the ability of glucose to compete with these redesigned PBA–diol crosslinks at its physiological concentration, thus improving responsiveness of the hydrogel network. Rheological analyses support enhanced sensitivity of these PBA–diol networks to glucose, while insulin release likewise improves from networks with reduced crosslink affinities. This work thus offers a new molecular design approach to improve glucose-responsive hydrogels for insulin delivery in diabetes management.

Substituent engineering is a key route to high-performance functional molecular materials in the same way as the development of a π-electron core for organic (opto-)electronics. Here we demonstrate a comparative study between aromatic phenyl- and aliphatic cyclohexyl-terminated side-chain substituents on an electron-deficient π-electron core, 3,4,9,10-benzo[de]isoquinolino[1,8-gh]quinolinetetracarboxylic diimide (BQQDI), to get insights into the impact of intermolecular interactions between the substituents in the solid state on high-performance electron-transport properties. In the BQQDI system, both phenyl- and cyclohexyl-terminated ethyl substituents show similar packing structures, demonstrating the unobvious impact of terminal groups. However, solution-processed single-crystal transistor studies revealed a relatively low electron mobility of cyclohexyl-terminated BQQDI. Based on molecular dynamics simulations, we attribute this discrepancy to dynamic molecular motions coupled with electronic coupling in the solid state. While phenyl groups in the phenylethyl substituent show intermolecular C–H⋯π interactions which lead to less dynamic motions, the cyclohexyl counterpart does not show any specific intermolecular interactions. Hence, a low-dynamic feature thanks to inter-side-chain interactions is promising for excellent charge-transport properties. The present findings underline the crucial role of interactions between substituents in the development of organic materials via side-chain-engineered control of the solid-state dynamic motions.

Herein, we have synthesized an ESIPT inbuilt novel tripodal gelator TH-AIL, which upon dissolution in DMSO followed by the addition of water (1 : 1) leads to the formation of a unique orange fluorescent organohydrogel (0.35% w/v, OHG). The obtained OHG reveals responses towards base NH₃ and acid HCl by way of reversible change in fluorescence colour from orange to green along with restorable conversion from gel to sol phase.

Astrovirus MLB2 (AstV-MLB2) is an emerging gastrointestinal virus causing meningitis and disseminated infections. Currently, there are no vaccine-based therapies available for AstV-MLB2. This study aims to develop multi-epitope vaccine models using candidate proteins from AstV-MLB2. Highly immunogenic epitopes (IC₅₀ < 200 μM) exhibiting conservation, antigenicity, and non-allergenicity were called from these proteins. Additionally, the selection criteria for epitopes were based on their potential to trigger immune cells and stimulate IFN-γ-mediated immune responses. The model vaccine constructs were designed from identified lead epitopes, along with immune-enhancer adjuvants and linker sequences. The proposed vaccine models were assessed for allergenicity, antigenicity, and structural integrity to ensure their safety and effectiveness. The binding potential of the vaccine models to HLA and TLR-4 immune cell receptors was evaluated to identify their capacity to stimulate immune responses. Among several raw constructs, MLB2-V1 and MLB2-V2 were identified as potential vaccine candidates due to their non-allergenic features, enhanced antigenic properties, and structural stability. Both these constructs were extensively evaluated and predicted to effectively bind to and interact with immune cell receptors, potentially triggering cellular and innate immune responses. Additionally, the prioritized constructs were deemed suitable for cloning and expression using recombinant DNA systems. The model vaccine constructs showed promise, warranting further investigation into their immune efficacy against MLB2-mediated infections through experimental assays and clinical trials.

Graph neural networks (GNN) have been demonstrated to correlate molecular structure with properties, enabling rapid evaluation of molecules for a given application. Molecular properties, including ground and excited states, are crucial to analyzing molecular behavior. However, while attention-based mechanisms and pooling methods have been optimized to accurately predict specific properties, no versatile models can predict diverse molecular properties. Here, we present graph neural networks that predict a wide range of properties with high accuracy. Model performance is high regardless of dataset size and origin. Further, we demonstrate an implementation of hierarchical pooling enabling high-accuracy prediction of excited state properties by effectively weighing aspects of features that correlate better with target properties. We show that graph attention networks consistently outperform convolution networks and linear regression, particularly for small dataset sizes. The graph attention model is more accurate than previous message-passing neural networks developed for the prediction of diverse molecular properties. Hence, the model is an efficient tool for screening and designing molecules for applications that require tuning multiple molecular properties.

Block copolymer (BCP) self-assembly leads to nanostructured materials with diverse ordered morphologies, some of which are attractive for transport applications. Multiblock AB copolymers are of interest as they offer a larger design parameter space than diblock copolymers allowing researchers to tailor their self-assembly to achieve target morphologies. In this study, we investigate the phase behavior of symmetric A_xB_yA_zB_yA_x and B_xA_yB_zA_yB_x pentablock copolymers (pentaBCPs) where A and B monomers have the same statistical segment length. We use a combination of self-consistent field theory (SCFT) calculations and molecular dynamics (MD) simulations to link the polymer design parameters, namely the fraction of middle block volume to the volume of all blocks of same type, τ, overall volume fraction of A block, f_A, and segregation strength, χN, to the equilibrium morphologies and the distributions of chain conformations in these morphologies. In the phase diagrams calculated using SCFT, we observe broader double gyroid windows and the existence of lamellar morphologies even at small values f_A in contrast to what has been seen for diblock copolymers. We also see a reentrant phase sequence of double gyroid → cylinder → lamellae → cylinder → double gyroid with increasing τ at fixed f_A. The chain conformations adopted in these morphologies are sampled in coarse-grained MD simulations and quantified with distributions of the chain end-to-end distance and fractions of chains whose middle (A or B) and end (A or B) blocks remain within domains of same chemistry (A or B). These analyses show that the pentaBCP chains adopt “looping”, “bridging”, and “hybrid” (both looping and bridging) conformations, with a majority of the chains adopting the hybrid conformation. The spatial distributions for each of the blocks in the pentaBCPs show that blocks of the same type in a chain locally segregate within the same domains, with shorter blocks segregating towards the domain boundaries and longer blocks filling the domain interior. This combined SCFT-MD approach enables us to rapidly screen the extensive pentaBCP design space to identify design rules for transport-favorable morphologies as well as verify the chain conformations and spatial arrangements associated with the theory predicted reentrant phase behavior.

Structural proteins like silk, squid ring teeth, elastin, collagen, or resilin, among others, are inspiring the development of new sustainable biopolymeric materials for applications including healthcare, food, soft robotics, or textiles. Furthermore, advances in the fields of soft materials and synthetic biology have a joint great potential to guide the design of novel structural proteins, despite both fields progressing mostly in a separate fashion so far. Using recombinant DNA technologies and microbial fermentations, we can design new structural proteins with monomer-level sequence control and a dispersity of ca. 1.0, based on permutations of tandem repeats derived from natural structural proteins. However, the molecular design of recombinant and repetitive structural proteins is a nontrivial task that is generally approached using low-throughput trial-and-error experimentation. Here, we review recent progress in this area, in terms of structure–function relationships and DNA synthesis technologies. We also discuss experimental and computational advances towards the establishment of rapid prototyping pipelines for this family of biopolymers. Finally, we highlight future challenges to make protein-based materials a commercially viable alternative to current fossil-based polymers.

Peptides are naturally potent and selective therapeutics with massive potential; however, low cell membrane permeability limits their clinical implementation, particularly for hydrophilic, anionic peptides with intracellular targets. To overcome this limitation, esterification of anionic carboxylic acids on therapeutic peptides can simultaneously increase hydrophobicity and net charge to facilitate cell internalization, whereafter installed esters can be cleaved hydrolytically to restore activity. To date, however, most esterified therapeutics contain either a single esterification site or multiple esters randomly incorporated on multiple sites. This investigation provides molecular engineering insight into how the number and position of esters installed onto the therapeutic peptide α carboxyl terminus 11 (αCT11, RPRPDDLEI) with 4 esterification sites affect hydrophobicity and the hydrolysis process that reverts the peptide to its original form. After installing methyl esters onto αCT11 using Fischer esterification, we isolated 5 distinct products and used 2D nuclear magnetic resonance spectroscopy, reverse-phase high performance liquid chromatography, and mass spectrometry to determine which residues were esterified in each and the resulting increase in hydrophobicity. We found esterifying the C-terminal isoleucine to impart the largest increase in hydrophobicity. Monitoring ester hydrolysis showed the C-terminal isoleucine ester to be the most hydrolytically stable, followed by the glutamic acid, whereas esters on aspartic acids hydrolyze rapidly. LC-MS revealed the formation of transient intramolecular aspartimides prior to hydrolysis to carboxylic acids. In vitro proof-of-concept experiments showed esterifying αCT11 to increase cell migration into a scratch, highlighting the potential of multi-site esterification as a tunable, reversible strategy to enable the delivery of therapeutic peptides.

Metal–organic frameworks (MOFs) are promising platforms for designing photoresponsive materials due to their structural versatility and tunable properties. However, challenges remain in fine-tuning the photoresponsive behavior while maintaining the high stability of MOFs. In this study, we synthesized a MOF containing redox-active pyromellitic diimide (PMDI) groups and unsaturated Zr₆ clusters named Zr-PMDI-DMF and fine-tuned its photochromic properties by exchanging the coordination solvent molecules on the Zr sites. Unlike traditional Zr₆ clusters with bidentate carboxylate coordination, Zr-PMDI-DMF features monodentate carboxylate coordination with the exposed Zr sites occupied by solvent molecules. We post-synthetically exchanged the coordinated N,N-dimethylformamide (DMF) solvent molecules with 2-(dimethylamino)ethanol (DMAE), N-methyltetrahydropyrrole (NMP), and dimethyl sulfoxide (DMSO) and determined the structures of the coordinated solvent molecules using single-crystal X-ray diffraction. Through photochromic and bleaching cycle experiments, electron paramagnetic resonance spectroscopy, and density functional theory calculations, we found that the coordinated solvents act as electron donors. In contrast, PMDI ligands act as electron acceptors, causing intra-framework electron transfer and photochromism. The rate of the photochromic response correlated with the electron-donating ability of the solvents, following the trend of DMAE > NMP > DMSO > DMF.