Molecular Systems Design & Engineering最新文献

Human cytochrome c (hCyt c) contains a covalently attached heme group with six-coordination (Met/His) and plays vital biological functions, including electron transfer and peroxidase activity by structural alterations, as well as other functions by interactions with partners such as neuroglobin (Ngb). In this study, we designed and engineered an artificial disulfide bond in hCyt c via double mutations (A51C/G77C) which bridges the Ω-loops C and D. The formation of the intramolecular disulfide bond (Cys51–Cys77) was confirmed by mass spectrometry. The molecular modeling study showed that the disulfide bond did not alter the overall structure, and the local structure where Cys51 was located was well folded into an α-helix. Spectroscopic studies were also performed to probe the effects of the disulfide bond on the protein structure, which revealed that the heme coordination of Met80 was likely weakened. Consequently, the rate of ligand binding and the peroxidase activity were enhanced. Meanwhile, the interaction between hCyt c and Ngb was weakened, as suggested by titration studies. These observations indicate that the dynamic properties of Ω-loops C and D may favor the heme coordination and protein–protein interactions by conformational change, which supports the native functions of hCyt c.

In this study, the effects of the substituent and solvent on the photophysical properties of the designed ESIPT active as well as donor–acceptor structured unsymmetrical azine dyes L1–L5 (R1–5 = –H, –NH₂, –OCH₃, –CF₃ and –CN, respectively) were investigated at PBE0/6-31++G(d,p) and CAM-B3LYP/6-31++G(d,p) levels of theory in the gas phase and three solvent media. The structural parameters, relative energies, vibrational spectra, photophysical properties, potential energy curves, natural bond orbital (NBO) charges, charge transfer (CT) indices, electron density properties, and reduced density gradient (RDG) spikes were computed. The results of vibrational spectra, structural parameters and electron density analysis demonstrated that the O–H⋯N H-bonding interaction is strengthened in all dyes upon photoexcitation from the S₀ to S₁ state which can facilitate the ESIPT process. All dyes exhibited both enol and keto emissions, in good agreement with the reported experimental results. The largest Stokes shift for keto emissions in solvent media was observed in MeOH solvent and is in the order 143 nm (L5) > 138 (L4) > 133 (L1) > 120 (L3) > 115 (L2) at the PBE0/6-31++G(d,p) level of theory. Introducing electron-withdrawing groups can increase the absorption and emission wavelengths as well as the red shift in fluorescence emission of L4 and L5, but hinder the occurrence of the ESIPT process compared with L2 and L3. The results demonstrated that the substituent effect is more significant in changing the molecular optical properties than the solvent effect. Our designed ESIPT molecules can simultaneously show enol and keto emissions and thus can be regarded as candidates to design single-molecule white-light emission materials.

Hard carbon is one of the most promising anode materials for sodium-ion batteries (SIBs). Biomass-derived hard carbon is deemed to be a good choice because of its superior material properties, abundance source, and cost advantages. This work used Physalis alkekengi L.'s husks as precursors to prepare a series of hard carbon materials via a pyrolysis method. It was found that the carbonization temperature is closely linked to the lattice characteristics of PLH-derived hard carbon. Higher temperatures promote the degree of graphitization of the lattice, which produces a smaller carbon interlayer spacing. The optimal sample demonstrated a high electrochemical performance and good reaction kinetics. It maintained a capacity of 291.6 mA h g⁻¹ after 100 cycles at 0.1 A g⁻¹ and delivered an average capacity of 61.9 mA h g⁻¹ at a high rate of 2.0 A g⁻¹. Furthermore, a full cell assembled using the optimal sample as an anode and Na₃V₂(PO₄)₃ as a cathode gave a high reversible capacity of 161.9 mA h g⁻¹ at 0.1 A g⁻¹ after 100 cycles.

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.

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.

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.

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.