Molecular Systems Design & Engineering最新文献

The binding of the receptor binding domain (RBD) of spike protein to the human ACE2 receptor is the primary step in the SARS-CoV-2 infection process. Spike protein has been an important therapeutic target. Emerging variants of SARS-CoV-2 have been imposing a significant challenge. Variants, especially with mutations on the RBD of spike protein, provide enhanced affinity towards the hACE2 receptor compared to the wild-type. Despite the development of many therapeutics, their efficacy towards the variants remains poor. In the present study, we used a fragment replacement approach to probe the fragment's space for analog design. We screened various fragments based on the geometric requirements to fit within the specified local environments of the RBD–ACE2 complex. Among all the screened analogs, two showed a better binding affinity with the RBD–ACE2 complex of the P.1 variant. Our all-atom simulations and free-energy calculations revealed a stable interaction of analogs with the interface residues of the RBD–ACE2 complex. The binding of analogs influenced the interactions of the key residues and led to structural interference in the complex. Essential dynamics analysis revealed that both analogs induce a change in the dynamic motion throughout the complex. The designed analogs may modulate the dynamics of the RBD–ACE2 complex formation and can be used as one of the lead molecules to interfere with the initial infection process of COVID-19 infections.

While the rise of superbugs and new resistance mechanisms continues decreasing the effectiveness of classical antibiotics, antimicrobial peptides (AMPs) are emerging as a new class of antimicrobials. Still, several drawbacks limit their transition to the clinic, including high production cost, haemolytic activity and possible inactivation by proteases. Here, we give an overview of the most recent work on short AMPs, which are currently a minority in the AMP databases, and of the main AMP design rules, describing their application for short sequences. We also summarize the techniques that can serve to investigate the key steps of the antimicrobial action and that can aid in the engineering of a tuned AMP interaction with bacterial barriers. Particular emphasis is given to the relationship between peptide sequence features and interfacial behaviour, highlighting the role of AMPs self-assembly in the interaction with membranes and their antimicrobial activity.

A mixed-ligand metal–organic framework (MOF) material composed of both amine- and hydroxyl-bearing linkers, KSU-1, was reacted with a variety of isocyanates. The hydroxyl groups reacted to a greater extent than the amines, in conflict with the previously observed relative nucleophilicities of these functionalities in the same MOF. When immobilized individually in monofunctional MOFs, the amine-functionalized linker was more reactive than the hydroxyl linker, indicating that the reactivity reversal observed in KSU-1 is due to the groups' mutual confinement within the MOF.

Chondroitin is a natural occurring glycosaminoglycan with applications as a nutraceutical and pharmaceutical ingredient and can be extracted from animal tissues. Microbial chondroitin-like polysaccharides emerged as a safer and more sustainable alternative source. However, chondroitin titers using either natural or recombinant microorganisms are still far from meeting the increasing demand. The use of genome-scale models and computational predictions can assist the design of microbial cell factories with possible improved titers of these value-added compounds. Genome-scale models have been herein used for the first time to predict genetic modifications in Escherichia coli engineered strains that would potentially lead to improved chondroitin production. Additionally, using synthetic biology approaches, a pathway for producing chondroitin has been designed and engineered in E. coli. Afterwards, the most promising mutants identified based on bioinformatics predictions were constructed and evaluated for chondroitin production in flask fermentation. This resulted in the production of 118 mg L⁻¹ of extracellular chondroitin by overexpressing both superoxide dismutase (sodA) and a lytic murein transglycosylase (mltB). Then, batch and fed-batch fermentations at the bioreactor scale were also evaluated, in which the mutant overexpressing mltB led to an extracellular chondroitin production of 427 mg L⁻¹ and 535 mg L⁻¹, respectively. The computational approach herein described identified several potential novel targets for improved chondroitin biosynthesis, which may ultimately lead to a more efficient production of this glycosaminoglycan.

The development of structurally controlled techniques inspired by the structural formation of living systems is of great importance for the fabrication of next-generation functional soft materials using environmentally friendly processes. This study aimed to investigate the formation mechanism of anisotropic structures of the gelatin network in a hydrogel through self-assembly on oriented templates. The effects of the oriented template having a uniaxially oriented surface on the anisotropic structure of the gelatin network were influenced by the structure at different scales: molecular (the secondary structure as the microstructure on the gelatin molecule) and molecular-assembled (the morphology of the gelatin network) scales. The mechanical properties and swelling behavior of the prepared gelatin hydrogels were characterized based on the anisotropic gelatin networks. The formation of an anisotropic gelatin network by self-assembly on the oriented template was presumably achieved by a two-step process due to the following two types of structural control factors: (1) the strength of the interaction between the template and gelatin molecules, and (2) the phase separation between the gelatin and water molecules induced during the hydrogelation process. The first process involves the formation of a thin molecular layer by the interaction between the template and gelatin molecules. The second process involves phase separation between the gelatin and water molecules during the cooling process of hydrogelation. These structurally controlled techniques for the formation of polymer networks inspired by biomineralization have two application prospects, which are the construction of biological tissue-like soft materials with complex hierarchical and anisotropic network structures through self-assembly processes, and expression of biological tissue-like functions.

The story of machine learning in general, and its application to molecular design in particular, has been a tale of evolving representations of data. Understanding the implications of the use of a particular representation – including the existence of so-called ‘activity cliffs’ for cheminformatics models – is the key to their successful use for molecular discovery. In this work we present a physics-inspired methodology which exploits analogies between model response surfaces and energy landscapes to richly describe the relationship between the representation and the model. From these similarities, a metric emerges which is analogous to the commonly used frustration metric from the chemical physics community. This new property shows state-of-the-art prediction of model error, whilst belonging to a novel class of roughness measure that extends beyond the known data allowing the trivial identification of activity cliffs even in the absence of related training or evaluation data.

Photothermal cancer therapy has gained increasing attention as a minimally invasive treatment via the localized heating of photothermal agents to eradicate cancer cells. However, its clinical translation has been limited by insufficient photothermal conversion in the near-infrared (NIR) range and low tumor-targeting efficiency. Here, synthetic melanin-like nanoparticles (∼190 nm in diameter) decorated with a cluster of smaller gold nanoparticles (∼20 nm in diameter) are developed as efficient NIR photothermal agents for in vivo cancer treatment. The melanin-gold hybrid nanoparticles are prepared by the oxidative polymerization of dopamine into colloidal melanin-like nanoparticles, followed by the spontaneous reduction of gold ion precursors into plasmonic nanoparticles on the surface of melanin nanoparticles. The gold nanoparticles significantly increase the NIR light absorption and photothermal conversion of the melanin nanoparticles, making their overall photothermal performance superior to conventional gold nanorods. Chemical conjugation of epidermal growth factor to the hybrid nanoparticles facilitates their cellular internalization into lung adenocarcinoma cells and enables in vivo tumor-targeting in a xenograft mouse model. The nanoparticles also exhibit excellent dispersion stability in serum and maintain high photothermal efficiency even after extensive laser irradiation. Our results suggest that the electronic hybridization of melanin and gold nanostructures provides a new opportunity to fine-tune their optical and chemical properties for tumor-targeted photothermal therapy.

Cooperativity in hydrogen bonds can be crucial for the stabilization of supramolecular systems. In this contribution, we propose a simple covalent modification within a pyrazole-based trimeric rosette that significantly improves its binding strength. Using dispersion-corrected density functional theory, at the BLYP-D3(BJ)/6-311++(d,p) level, we show how an intramolecular hydrogen bond acts as a bridge between an electron-donating group and an electron-withdrawing group by moving the electron density from one group to the other one through the sigma electron system. This effect strongly enhances the inductive ability of the substituents, and further increases the synergy of the cyclic trimer.

Atmospheric corrosion, an electrochemical phenomenon, initiates the degradation of materials, primarily metals, through their interaction with environmental droplets or aerosols. This degradation extends to various aspects such as material performance, longevity, and safety, emphasizing the critical need to comprehend and inhibit corrosion, particularly in industrial and environmental settings. Structural aluminum alloys, prominently used in aerospace, automotive, and marine industries, undergo extensive scrutiny due to their susceptibility to atmospheric corrosion. Nonetheless, the absence of suitable electrochemical techniques capable of accommodating droplet volumes underscores the urgent need for advancements in corrosion research. This paper introduces an innovative and efficient multielectrode cell setup aimed at rapid screening of droplet and thin film electrolyte volumes, presenting a new high-throughput screening method. Utilizing AA6014 as a substrate, this paper demonstrates a proof of concept for this methodology. It explores the influence of a crucial parameter, pH, while considering the effects of evaporation and secondary spreading. Various organic corrosion inhibitors, including some well-known inhibitors, were examined to evaluate the impact of chemically related structures on inhibition efficiency. This investigation predominately focuses on comparing and discussing differences and similarities in inhibition performance between bulk and droplet volumes. Ultimately, this comprehensive investigation aims to enhance the understanding and management of corrosion inhibition in droplet and thin film environments.

The feasibilities of the chemical reactions of indoline were analyzed with density functional theory (DFT) simulation. A series of azo disperse dyes using indoline as a coupling component were synthesized, namely D1–D6. The synthesized dyes were investigated by UV-visible, FT-IR, ¹H-NMR and MS spectroscopies. DFT simulation was applied to analyze the spectrometric properties of designed dyes. The dyeing of polyethylene terephthalate (PET) and nylon (PA) fabrics were assessed and compared. The synthesized indoline azo disperse dyes exhibited a yellow to red hue on the PET and PA fabrics. Deep shades were achieved with increased dye concentrations for D1 and D2 for the PET and PA fabrics. Excellent rubbing fastness and good sublimation fastness were achieved. Interrelations between dye structures and dyeing performance on the PET and PA fabrics were investigated using DFT calculations.