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The multiple relaxation processes of excited states are a bridge connecting molecular structures and properties, providing enormous application potential for organic luminogens. However, a systematic understanding and manipulation of the relationship between the molecular structure, excited state relaxation processes, and properties of organic luminogens is still lacking. Herein, we report a strategy for manipulating excited state electronic configurations through the regulation of the sulfur oxidation state to construct eminent organic type I PSs. Combined with the experimental results and theoretical calculations, we have successfully revealed the decisive role of high sulfur oxidation states in promoting ROS production capacity. Impressively, a higher sulfur oxidation state can reduce the singlet-triplet energy gap (ΔE ST), increase the matching degree of transition configurations, promote the changes of the excited state electronic configurations, and boost the effective ISC proportion by enhancing intramolecular interactions. Therefore, DBTS2O with the highest sulfur oxidation state exhibits the strongest type I ROS generation ability. Additionally, guided by our strategy, a water-soluble PS (2OA) is designed and synthesized, showing selective imaging capacity and photokilling ability against Gram-positive bacteria. This study broadens the horizons for both molecular design and mechanism study of high-performance organic type I PSs.
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We designed two series of NIR-II PTAs with D-A or D-A-D structures, in which the introduction of thiophene promotes a bathochromic shift of emission into the NIR-II region, helps to improve the cellular uptake of the PTAs and facilitates NIR-II imaging-guided PDT/PTT cancer phototherapy.
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Exploring the molecular packing and interaction between chiral molecules, no matter single enantiomer or racemates, is important for recognition and resolution of chiral drugs. However, sensitive and non-destructive analysis methods are lacking. Herein, an intermolecular-charge transfer (ICT) based spectroscopy is reported to reveal the differences in interaction between the achiral acceptor 1,2,4,5-tetracyanobenzene (TCNB) and the chiral donors, including S, R, and racemic naproxen (S/R/rac-NAP). In this process, S-NAP+TCNB and R-NAP+TCNB display a narrower band gap attributed to the newly formed ICT state. In contrast, the mixed rac-NAP and TCNB exhibit almost no significant change due to the strong affinity between the stereoisomers according to the Wallach's rule. Thus, S/R-NAP can be easily distinguished from rac-NAP based on significantly different optical behavior. The single crystal analysis, infrared spectroscopy, fluorescence spectroscopy, and theoretical calculation of naproxen confirm the importance of carboxyl for this differentiation in molecular packing and interaction. In addition, the esterification derivatization of naproxen achieves the manipulation of the intermolecular interaction model of racemates from the absolute Wallach's rule to a coexisting form of Wallach's rule and ICT. Further, visualized chiral purification of naproxen by the simple cocrystallization method is achieved through the collaboration of ICT and Wallach's rule.
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While second near-infrared (NIR-II) fluorescence imaging is a promising tool for real-time surveillance of surgical operations, the previously reported organic NIR-II luminescent materials for in vivo imaging are predominantly activated by expensive lasers or X-ray with high power and poor illumination homogeneity, which significantly limits their clinical applications. Here we report a white-light activatable NIR-II organic imaging agent by taking advantages of the strong intramolecular/intermolecular D-A interactions of conjugated Y6CT molecules in nanoparticles (Y6CT-NPs), with the brightness of as high as 13315.1, which is over two times that of the brightest laser-activated NIR-II organic contrast agents reported thus far. Upon white-light activation, Y6CT-NPs can achieve not only in vivo imaging of hepatic ischemia reperfusion, but also real-time monitoring of kidney transplantation surgery. During the surgery, identification of the renal vasculature, post-reconstruction assessment of renal allograft vascular integrity, and blood supply analysis of the ureter can be vividly depicted by using Y6CT-NPs with high signal-to-noise ratios upon clinical laparoscopic LED white-light activation. Our work provides efficient molecular design guidelines towards white-light activatable imaging agent and highlights an opportunity for precision imaging theranostics.
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Imagem Óptica , Cirurgia Assistida por Computador , Animais , Cirurgia Assistida por Computador/métodos , Camundongos , Imagem Óptica/métodos , Luz , Nanoestruturas/química , Transplante de Rim/métodos , Humanos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Nanopartículas/química , Raios Infravermelhos , Luminescência , Rim/diagnóstico por imagem , Rim/cirurgia , Masculino , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Meios de Contraste/químicaRESUMO
Fluorescence imaging-guided photodynamic therapy (PDT) has attracted extensive attention due to its potential of real-time monitoring the lesion locations and visualizing the treatment process with high sensitivity and resolution. Aggregation-induced emission luminogens (AIEgens) show enhanced fluorescence and reactive oxygen species (ROS) generation after cellular uptake, giving them significant advantages in bioimaging and PDT applications. However, most AIEgens are unfavorable for the application in organisms due to their severe hydrophobicity. Anion-π+ type AIEgens carry intrinsic charges that can effectively alleviate their hydrophobicity and improve their binding capability to cells, which is expected to enhance the bioimaging quality and PDT performance. This concept summarizes the applications of anion-π+ type AIEgens in fluorescence imaging, fluorescence imaging-guided photodynamic anticancer and antimicrobial therapy in recent years, hoping to provide some new ideas for the construction of robust photosensitizers. Finally, the current problems and future challenges of anion-π+ AIEgens are discussed.
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Ânions , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Humanos , Ânions/química , Espécies Reativas de Oxigênio/metabolismo , Corantes Fluorescentes/química , Interações Hidrofóbicas e Hidrofílicas , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagemRESUMO
The low oxygen dependence of type I photosensitizers (PSs) has made them a popular choice for treating solid tumors. However, the drawbacks of poor water solubility, short emission wavelength, poor stability, and inability to distinguish cancer cells from normal cells limit the application of most type I PSs in clinical therapy. Thereby, developing novel type I PSs for overcoming these problems is an urgent but challenging task. Herein, by utilizing the distinctive structural characteristics of anion-π+ interactions, a highly water-soluble typeâ I PS (DPBC-Br) with aggregation-induced emission (AIE) characteristic and near-infrared (NIR) emission is fabricated for the first time. DPBC-Br displays remarkable water solubility (7.3â mM) and outstanding photobleaching resistance, enabling efficient and precise differentiation between tumor cells and normal cells in a wash-free and long-term tracking manner via NIR-I imaging. Additionally, the superior typeâ I reactive oxygen species (ROS) produced by DPBC-Br provide both specific killing of cancer cells in vitro and inhibition of tumor growth in vivo, with negligible systemic toxicity. This study rationally constructs a highly water-soluble typeâ I PS, which has higher reliability and controllability compared with conventional nanoparticle formulating procedures, offering great potential for clinical cancer treatment.
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Neoplasias , Fotoquimioterapia , Humanos , Água , Reprodutibilidade dos Testes , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Diagnóstico por Imagem , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Espécies Reativas de OxigênioRESUMO
Type I photosensitizers (PSs) with an aggregation-induced emission (AIE) feature have received sustained attention for their excellent theranostic performance in the treatment of clinical diseases. However, the development of AIE-active type I PSs with strong reactive oxygen species (ROS) production capacity remains a challenge due to the lack of in-depth theoretical studies on the aggregate behavior of PSs and rational design strategies. Herein, we proposed a facile oxidization strategy to enhance the ROS generation efficiency of AIE-active type I PSs. Two AIE luminogens, MPD and its oxidized product MPD-O were synthesized. Compared with MPD, the zwitterionic MPD-O showed higher ROS generation efficiency. The introduction of electron-withdrawing oxygen atoms results in the formation of intermolecular hydrogen bonds in the molecular stacking of MPD-O, which endowed MPD-O with more tightly packed arrangement in the aggregate state. Theoretical calculations demonstrated that more accessible intersystem crossing (ISC) channels and larger spin-orbit coupling (SOC) constants provide further explanation for the superior ROS generation efficiency of MPD-O, which evidenced the effectiveness of enhancing the ROS production ability by the oxidization strategy. Moreover, DAPD-O, a cationic derivative of MPD-O, was further synthesized to improve the antibacterial activity of MPD-O, showing excellent photodynamic antibacterial performance against methicillin-resistant S. aureus both in vitro and in vivo. This work elucidates the mechanism of the oxidization strategy for enhancing the ROS production ability of PSs and offers a new guideline for the exploitation of AIE-active type I PSs.
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A quadrupolar compound Pyr-BA with two pyrrole-type nitrogen atoms doped externally was prepared in this work. In high contrast with other π ionic radicals, its cationic radical Pyr-BAâ + undergoes unusual symmetry-broken charge separation (SB-CS), generating the mixed valence complex of Pyr-BA+1-q â â â Pyr-BA+1+q , where q is the degree of charge transfer. Variable-temperature (VT) single-crystal analysis, absorption and EPR experiments all confirmed that aggregation and lower temperature would help to facilitate this SB-CS process. Gibbs energy calculations and gauge-including magnetically induced current simulation both validate that, for Pyr-BAâ + , SB-CS behavior is more favorable than the conventional dimerization mode. To the best of our knowledge, this is the first study that shows solid single-crystal evidence for spontaneous SB-CS between identical ionic radicals. Such a unique phenomenon is of great significance both in terms of fundamental aspects and uncharted material science.
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Incorporating two pyrrole subunits at the bay positions of perylene-diimide has been a long-pursued goal since 2009, but it has not been achieved due to high strain. Herein, via one step Buchwald-Hartwig reaction, PDI-2N was successfully generated with a bowl depth of 1.52 Å. Though with electron-rich pyrrole embedding, PDI-2N's radical anion and dianion were facilely prepared and were investigated both experimentally and theoretically. Moreover, PDI-2N crystallized in different manners under distinct conditions, and it formed tubular crystals with infinite two-directional columnar stacking under DMF conditions. This finding develops a dream bowl-shaped PDI derivative that holds great promise in organoelectronics.
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In this work, nitrogen-annulated perylene (NP) was dimerized into one framework connected by two nitrogen atoms, generating the target molecule of DNP-DA. Owing to the substructure of 1,6-diazecine ten-membered ring, DNP-DA illustrates helical chirality with moderate dissymmetry factor, elevated molecular levels, expanded conjugation and supramolecular interactions with acceptors etc. Notably, DNP-DA represents a limited example of nitrogen-perylene based CPL emitter with glum around 6×10-3 . Intrigued by the facile fabrication via a simple amination-cross coupling sequence and other above advancing features, this work demonstrates the potential generality of utilizing 1,6-diazecine as a chiral unit to build CPL-active materials.
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This article proposes a distributed adaptive fault-tolerant formation-containment control with prescribed performance for heterogeneous multiagent systems (MASs) consisting of multiple unmanned aerial vehicles (UAVs) and unmanned ground vehicles (UGVs) in the presence of actuator faults. First, utilizing the neighborhood formation error information, the distributed fault-tolerant formation control strategy is developed for the trajectory dynamics of each UAV to achieve the formation tracking, that is, all UAVs track the virtual leader and perform the prespecified formation configuration. Then, the adaptive fault-tolerant containment algorithm, independent of the positions of the leaders, is proposed to guarantee the UGVs converge to the convex hull formed by the leader UAVs. The adaptive estimation scheme is constructed to compensate for the unknown system parameters and actuator loss-of-effectiveness and bias faults. The formation-containment tracking performance is analyzed based on Lyapunov theory with the synchronization errors satisfying the prescribed performance. A simulation example based on UAVs-UGVs systems is adopted to verify the effectiveness of the proposed control strategy.
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Pathogenic bacteria infections, especially multidrug resistant bacteria infections have aroused worldwide attention due to their severe threats to human beings. Thus, the development of highly effective antibacterial reagents is very important. However, the design of antimicrobials is still quite challenging for the lack of a universal design strategy. Here, a synergistic manipulation strategy of dipole-dipole and anion-π+ interaction is proposed for constructing highly efficient antimicrobials with aggregation-induced emission (AIE) feature. Firstly, four anion-π+ -type AIE luminogens were designed and synthesized. Due to the electron-donating and hydrophilic characteristic of methoxy groups, 3MOTPO containing three methoxy groups showed the largest dipole moment (5.06 Debye) and dual anion-π+ interactions in the solid state. Driven by both dipole-dipole and anion-π+ interactions, 3MOTPO showed the strongest bacterial binding ability and the best antibacterial activities (MIC90 =3.76â µM). The work offers a deep insight into the rational design of highly efficient antimicrobials for luminescence-guided antibacterial study.
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Antibacterianos , Anti-Infecciosos , Humanos , Antibacterianos/farmacologia , Ânions , Luminescência , BactériasRESUMO
Near-infrared (NIR) photosensitizers with rapid reactive oxygen species (ROS) production ability are in great demand owing to their promising performance toward boosting photodynamic therapy (PDT) and deep-tissue imaging, but molecular design guidelines for efficient photosensitizers are rarely elucidated. Herein, three AIEgens named DBP, TBP, and TBP-SO3 are designed and synthesized by precise donor-acceptor (D-A) molecular engineering to deeply understand the structure-property-application relationships. All the compounds exhibit AIE characteristics with strong long-wavelength emission in the aggregated state and are capable of efficiently producing ROS under white light irradiation. By controlling the ability of the D-A units, TBP-SO3 realizes NIR emission and more rapid ROS generation ability due to the promoted intersystem crossing processes compared with those of DBP and TBP. In addition, NIR-emitting TBP-SO3 is capable of specific endoplasmic reticulum targeting and excellent PDT treatment ability of cancer cells and bacteria. This successful example of molecular engineering paves a valuable way for developing advanced PSs with AIE properties, efficient ROS generation ability, and intense emission for fluorescence imaging PDT.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Luz , Imagem Óptica , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de OxigênioRESUMO
Ovalene's nitrogenated derivative with all zigzag edges and nitrogen atom doping at the periphery has been developed via one-step nitrogenation of formylbisanthene. Because of nitrogen incorporation, these molecules show greatly decreased highest occupied molecular orbital levels, enhanced intermolecular interactions, and a reversible acid response. Aza-ovalene also exhibits a diatropic ring current along the periphery. This work provides rare examples of all-zigzag-edged N-polycyclic aromatic hydrocarbons.
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Catalytic efficiency and thermostability are the two most important characteristics of enzymes. However, it is always tough to improve both catalytic efficiency and thermostability of enzymes simultaneously. In the present study, a computational strategy with double-screening steps was proposed to simultaneously improve both catalysis efficiency and thermostability of enzymes; and a fungal α-l-rhamnosidase was used to validate the strategy. As the result, by molecular docking and sequence alignment analysis within the binding pocket, seven mutant candidates were predicted with better catalytic efficiency. By energy variety analysis, A355N, S356Y, and D525N among the seven mutant candidates were predicted with better thermostability. The expression and characterization results showed the mutant D525N had significant improvements in both enzyme activity and thermostability. Molecular dynamics simulations indicated that the mutations located within the 5 Å range of the catalytic domain, which could improve root mean squared deviation, electrostatic, Van der Waal interaction, and polar salvation values, and formed water bridge between the substrate and the enzyme. The study indicated that the computational strategy based on the binding energy, conservation degree and mutation energy analyses was effective to develop enzymes with better catalysis and thermostability, providing practical approach for developing industrial enzymes.
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Aspergillus niger , Proteínas Fúngicas , Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Engenharia de Proteínas , Aspergillus niger/enzimologia , Aspergillus niger/genética , Catálise , Estabilidade Enzimática/ética , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genéticaRESUMO
α-L-Rhamnosidase has attracted lots of attention due to its industrial potential applications. The applicability of α-L-rhamnosidase, however, was limited by their low ligand affinity on the industrial scale. In order to improve the affinity of α-L-rhamnosidase for industrial use, we investigated the variation of its affinity by amino acid replacement. Particularly, the enzyme affinity of a α-L-rhamnosidase from Aspergillus niger JMU-TS528 (rRha1) was measured with the semi-conservative amino acid (homology between 30% -80%) replaced. As a result, the enzyme affinity of the two mutants, R404S and N578D, were increased by 1.45-fold and 2.3-fold, respectively, showing that these two mutants could be the promising candidates for industrial use. To test if these mutations bring negative effect on the enzyme properties, we also determined the other enzymatic properties of these mutants and showed no negative effect. To understand the improvement of enzyme affinity, the conformational flexibility of (α/α)6-barrel catalytic domain were examined by molecular dynamics (MD) simulation, and demonstrated that the conformations of these mutants are more flexible, which could influence the affinity of substrates to the enzyme and hence the enzyme activity. This work not only enhanced the enzyme affinity of a α-L-rhamnosidase, making rRha1 a promising candidate for industrial processes, but also provided an effective technical strategy for improving affinity of other enzymes.
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Aspergillus niger/enzimologia , Domínio Catalítico , Sequência Conservada , Glicosídeo Hidrolases/química , Aspergillus niger/genética , Sítios de Ligação , Domínio Catalítico/genética , Ativação Enzimática , Expressão Gênica , Glicosídeo Hidrolases/genética , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
α-l-Rhamnosidase is a biotechnologically important enzyme in food industry and in the preparation of drugs and drug precursors. To expand the functionality of our previously cloned α-l-rhamnosidase from Aspergillus niger JMU-TS528, 14 mutants were constructed based on the changes of the folding free energy (ΔΔG), predicted by the PoPMuSiC algorithm. Among them, six single-site mutants displayed higher thermal stability than wild type (WT). The combinational mutant K573V-E631F displayed even higher thermostability than six single-site mutants. The spectra analyses displayed that the WT and K573V-E631F had almost similar secondary and tertiary structure profiles. The simulated protein structure-based interaction analysis and molecular dynamics calculation were further implemented to assess the conformational preferences of the K573V-E631F. The improved thermostability of mutant K573V-E631F may be attributed to the introduction of new cation-π and hydrophobic interactions, and the overall improvement of the enzyme conformation. PRACTICAL APPLICATIONS: The stability of enzymes, particularly with regards to thermal stability remains a critical issue in industrial biotechnology and industrial processing generally tends to higher ambient temperature to inhibit microbial growth. Most of the α-l-rhamnosidases are usually active at temperature from 30 to 60°C, which are apt to denature at temperatures over 60°C. To expand the functionality of our previously cloned α-l-rhamnosidase from Aspergillus niger JMU-TS528, we used protein engineering methods to increase the thermal stability of the α-l-rhamnosidase. Practically, conducting reactions at high temperatures enhances the solubility of substrates and products, increases the reaction rate thus reducing the reaction time, and inhibits the growth of contaminating microorganisms. Thus, the improvement on the thermostability of α-l-rhamnosidase on the one hand can increase enzyme efficacy; on the other hand, the high ambient temperature would enhance the solubility of natural substrates of α-l-rhamnosidase, such as naringin, rutin, and hesperidin, which are poorly dissolved in water at room temperature. Protein thermal resistance is an important issue beyond its obvious industrial importance. The current study also helps in the structure-function relationship study of α-l-rhamnosidase.
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Aspergillus niger/enzimologia , Proteínas Fúngicas/química , Glicosídeo Hidrolases/química , Algoritmos , Aspergillus niger/química , Aspergillus niger/genética , Estabilidade Enzimática , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Temperatura Alta , Engenharia de ProteínasRESUMO
α-L-Rhamnosidase is a glycoside hydrolase capable of removing naringin from citrus juice. However, α-L-rhamnosidases always have broad substrate spectra, causing negative effects on citrus juice. In this study, a α-L-rhamnosidase-expressing fungal strain, JMU-TS529, was identified, and its α-L-rhamnosidase was characterized. As a result, JMU-TS529 was identified as Aspergillus tubingensis via morphological and molecular characteristics. The predicted protein sequence shared an amino acid identity of less than 30% with previously characterized α-L-rhamnosidases. The optimal pH and temperature were 4.0 and 50-60 °C, respectively. Most importantly, the α-L-rhamnosidase showed a strong ability to hydrolyze naringin but scarcely acted on other substrates. Furthermore, the enzyme could efficiently remove naringin from pomelo juice without changing its attractive aroma. These results indicate that the present enzyme represents a new clade of Aspergillus α-L-rhamnosidase that is desirable for debittering citrus juice, providing a better alternative for improving the quality of citrus juice.
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Aspergillus/enzimologia , Citrus/química , Sucos de Frutas e Vegetais/análise , Proteínas Fúngicas/química , Glicosídeo Hidrolases/química , Aspergillus/genética , Biocatálise , Estabilidade Enzimática , Manipulação de Alimentos , Frutas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Concentração de Íons de Hidrogênio , Hidrólise , TemperaturaRESUMO
To improve the thermostability of α-L-rhamnosidase (r-Rha1), an enzyme previously identified from Aspergillus niger JMU-TS528, multiple arginine (Arg) residues were introduced into the r-Rha1 sequence to replace several lysine (Lys) residues that located on the surface of the folded r-Rha1. Hinted by in silico analysis, five surface Lys residues (K134, K228, K406, K440, K573) were targeted to produce a list of 5 single-residue mutants and 4 multiple-residue mutants using site-directed mutagenesis. Among these mutants, a double Lys to Arg mutant, i.e. K406R/K573R, showed the best thermostability improvement. The half-life of this mutant's enzyme activity increased 3â¯h at 60⯰C, 23â¯min at 65⯰C, and 3.5â¯min at 70⯰C, when compared with the wild type. The simulated protein structure based interaction analysis and molecular dynamics calculation indicate that the thermostability improvement of the mutant K406R-K573R was possibly due to the extra hydrogen bonds, the additional cation-π interactions, and the relatively compact conformation. With the enhanced thermostability, the α-L-rhamnosidase mutant, K406R-K573R, has potentially broadened the r-Rha1 applications in food processing industry.