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Cytochrome P450 GcoA is an enzyme that catalyses the guaiacol unit of lignin during the lignin breakdown via aryl-O-demethylation reaction. This reaction is intriguing and is of commercial importance for its potential application in the production of biofuel and plastic from biomass feedstock. Recently, the F169A mutation in the P450 GcoA elicits a promiscuous activity for syringol while maintaining the native activity for guaiacol. Using comprehensive MD simulations and hybrid QM/MM calculations we address, herein, the origin of promiscuity in P450 GcoA and its relevance to the specific activity toward lignin-derived substrates. Our study shows a crucial role of an aromatic dyad, F169, and F395 through regulating the water access to the catalytic center. The F169A mutation opens a water aqueduct and hence increases the native activity for the G-lignin. We show that syringol binds very tightly in the WT enzyme which blocks the conformational rearrangement needed for the second step of O-demethylation. The F169A creates an extra room favoring the conformational rearrangement in the demethylated syringol (3MC) and second dose of the dioxygen insertion. Therefore, using MD simulations and complemented by thorough QM/MM calculations, our study shows how does a single site mutation re-architect active site engineering for promiscuous syringol activity.

Electron/proton transfers in water proceeding from ground/excited states are the elementary reactions of chemistry. These reactions of an iconic class of molecules─polypyridineRu(II)─are now controlled by capturing or releasing three of them with hosts that are shape-switchable. Reversible erection or collapse of the host walls allows such switchability. Some reaction rates are suppressed by factors of up to 120 by inclusive binding of the metal complexes. This puts nanometric coordination chemistry in a box that can be open or shut as necessary. Such second-sphere complexation can allow considerable control to be exerted on photocatalysis, electrocatalysis, and luminescent sensing involving polypyridineRu(II) compounds. The capturing states of hosts are symmetry-matched to guests for selective binding and display submicromolar affinities. A perching complex, which is an intermediate state between capturing and releasing states, is also demonstrated.

Improving the performance of CsPbI2Br PSCs by spinning BABr on 3D CsPbI2Br films to form 2D/3D heterostructures, and based on this, monolithic all-PTSCs are fabricated, realizing a pioneering exploration for the application of CsPbI2Br to all-PTSCs.

In this paper, we proposed an adaptive robust variable selection procedure for the logistic regression model. The proposed method is robust to outliers and considers the goodness-of-fit of the regression model. Furthermore, we apply an MM algorithm to solve the proposed optimization problem. Monte Carlo studies are evaluated the finite-sample performance of the proposed method. The results show that when there are outliers in the dataset or the distribution of covariate variable deviates from the normal distribution, the finite-sample performance of the proposed method is better than that of other existing methods.Finally, the proposed methodology is applied to the data analysis of Parkinson's disease.

Pt(II) complexes play an important role in bioinorganic chemistry due to their antitumor activities. In the present study, we focused on building predictive models for the hydrophobicity of Pt(II) complexes. A five-parameter model, integrating frontier orbital energies (EHOMO, ELUMO) and descriptors derived from electrostatic potentials on molecular surface, was firstly constructed by using multiple linear regression (MLR) method. Mechanistic interpretations of the introduced descriptors were elucidated in terms of intermolecular interactions in the n-octanol/water partition system. Then, four up-to-date modeling methods, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a very rigorous Monte Carlo cross-validation (MCCV) were performed to verify the reliability of the constructed models. The peak, median and integral values of the best GP model are 0.88, 0.86 and 0.84, respectively. The root mean squared errors for the test set (RMSEP) of the MLR, SVM, LSSVM and GP models fall in the range of 0.62–0.71. Although they are not superior to prior models built with the use of a number of descriptors, the results are satisfactory. Applicability domain of the model was evaluated.

The localization of photogenerated electrons in photovoltaic and photocatalytic materials is crucial for reducing the electron–hole recombination rate. Here, the photogenerated electron localization is systematically investigated on the CH3NH3PbI3 (MAPbI3) perovskite using first-principles calculations. It is found that under vacuum conditions, the photogenerated electron is delocalized in the MAPbI3 bulk as well as on the stochiometric MAPbI3(001) surface with the CH3NH3I (MAI) termination, while it is trapped on the defect-free PbI2-terminated surface. Our ab initio molecular dynamics simulations reveal that the introduction of solutions will prompt the formation of localized electronic states. The photogenerated electron is discovered to be localized on both the MAI- and PbI2-terminated surfaces in the presence of solutions with different concentrations of HI, from pure water to the saturated solution. We demonstrate that the Pb–I bond weakening or breaking resulting in an unsaturated coordination of a Pb site is the prerequisite to trap the photogenerated electron.

The supersaturated saline drilling fluid (SDF) with strong inhibition, as a novel alternative to anhydrite formation drilling, is crucial for the safe and economic drilling operation. In this work, a high performance supersaturated SDF was experimentally formulated in terms of the long anhydrite features of Missan Oilfields. Composite weighting approach involving liquid and solid materials was introduced to reinforce the inhibition of supersaturated SDF. A suite of laboratory tests was conducted to screen the essential viscosifiers and filtrate reducers, and optimize the formula of supersaturated SDF, by means of evaluating the basic rheological and filtration properties. The results showed that univalent salts, NaCl, KCl, and HCOONa, are utilized to formulate the multiple brine phase, and polymeric additives, VIS and S-FLO, can effectively improve rheology and filtration properties. The newly developed supersaturated SDF exhibits the excellent thermal stability, lubricity, as well as inhibition capability, which should be an instructive solution to minimize the hole problems in the anhydrite drilling.

Cytochrome P450 GcoA is an enzyme that catalyses the guaiacol unit of lignin during the lignin breakdown via aryl-O-demethylation reaction. This reaction is intriguing and is of commercial importance for its potential application in the production of biofuel and plastic from biomass feedstock. Recently, the F169A mutation in the P450 GcoA elicits a promiscuous activity for syringol while maintaining the native activity for guaiacol. Using comprehensive MD simulations and hybrid QM/MM calculations we address, herein, the origin of promiscuity in P450 GcoA and its relevance to the specific activity toward lignin-derived substrates. Our study shows a crucial role of an aromatic dyad, F169, and F395 through regulating the water access to the catalytic center. The F169A mutation opens a water aqueduct and hence increases the native activity for the G-lignin. We show that syringol binds very tightly in the WT enzyme which blocks the conformational rearrangement needed for the second step of O-demethylation. The F169A creates an extra room favoring the conformational rearrangement in the demethylated syringol (3MC) and second dose of the dioxygen insertion. Therefore, using MD simulations and complemented by thorough QM/MM calculations, our study shows how does a single site mutation re-architect active site engineering for promiscuous syringol activity.

Cytochrome P450 GcoA is an enzyme that catalyses the guaiacol unit of lignin during the lignin breakdown via aryl-O-demethylation reaction. This reaction is intriguing and is of commercial importance for its potential application in the production of biofuel and plastic from biomass feedstock. Recently, the F169A mutation in the P450 GcoA elicits a promiscuous activity for syringol while maintaining the native activity for guaiacol. Using comprehensive MD simulations and hybrid QM/MM calculations we address, herein, the origin of promiscuity in P450 GcoA and its relevance to the specific activity toward lignin-derived substrates. Our study shows a crucial role of an aromatic dyad, F169, and F395 through regulating the water access to the catalytic center. The F169A mutation opens a water aqueduct and hence increases the native activity for the G-lignin. We show that syringol binds very tightly in the WT enzyme which blocks the conformational rearrangement needed for the second step of O-demethylation. The F169A creates an extra room favoring the conformational rearrangement in the demethylated syringol (3MC) and second dose of the dioxygen insertion. Therefore, using MD simulations and complemented by thorough QM/MM calculations, our study shows how does a single site mutation re-architect active site engineering for promiscuous syringol activity.

Terpene synthases (TPS) catalyze the cyclization of the acyclic prenyl diphosphate precursor and are responsible for the abundance of the natural product terpene in nature. The biosynthesis of terpenoid by nonseed plant TPS is not well understood due to the highly dynamic feature of the cyclization reaction and the unavailability of the enzyme structure. Here we discovered a class I TPS JeST4 from Jungermannia exsertifolia and elucidated its catalytically active structure in complex with the substrate and the key carbocation intermediates during catalysis. We found that D106 is critical for the enzyme's activity by mediating the gate formed with R294 or R225. Further, we identified two hotspot regions from the coevolution study and computational simulations, and the G91S and R242K mutations improved the conversion rate by 39- and 11-fold, respectively. Remarkably, in both variants, R294 is able to stabilize the substrate pyrophosphate group, analogous to the dominating interaction network observed in the distantly related bacterial TPSs. Further, NMR and molecular dynamics simulations indicated the formation of an unusual C10(S)-bicyclogermacrene. Our research demonstrates the capacity of computing-informed engineering of nonseed plant TPS. The discovery of the new TPS enzyme from nonseed land plant and computing-guided engineering would potentiate the exploitation of the ultracheap enzyme as a potential biocatalyst for the production of the valuable terpenoid products.

The site-selective C–H oxidation of terpenoids by P450 attracts great attention because of their wide range of biological activities. However, the binding and catalytic mechanism of P450 for the hydroxylation of complex terpenoid substrates remains elusive, which has limited the rational engineering of P450 as a biocatalyst for terpenoid biosynthesis. Here, we studied the origin of the selectivity and reactivity of P450BM3 in the hydroxylation of terpenoids by combining molecular dynamics simulations and QM/MM calculations, using artemisinin as a model compound. We found that the conformational change of the β1 sheet at the substrate entrance and the displacement of the β′ helix were critical for reshaping the binding pocket to modulate substrate entrance and positioning the C–H to be activated toward the oxidative species of P450 for the subsequent hydrogen abstraction, the rate-determining step of hydroxylation. There is a distinct linear correlation between activation barriers and reaction coordinates, indicating that reaction coordinates can be used as a facile descriptor for predicting the reactivity of P450BM3. These findings would provide valuable guidance for predicting the selectivity and reactivity of P450BM3 for the selective hydroxylation of non-native terpenoid substrates so as to prioritize the rationally designed enzymes for terpenoid biosynthesis.

Exploring high efficiency, low cost and stable photocatalysts that enable full solar spectrum (UV, visible and near-infrared) utilization for photocatalytic hydrogen generation still faces huge challenge. Herein, a Co2P/CdS Z-scheme photocatalyst without noble metal is rationally fabricated to achieve ultrabroad UV-Vis-NIR-harvesting. Compared to Pt/CdS, CdS and Co2P, the optimized Co2P/CdS exhibits much more outstanding performance with the HER rate of 262.16, 66.98 and 3.93 mmol/g/h under solar, visible (780 nm > λ > 420 nm) and NIR (λ > 780 nm) light, respectively. Particularly, 10% Co2P/CdS displays a prominent AQE value of 2.26% at 700 nm. The Z-scheme transform route can effectively enhance the separation of charge carriers in Co2P/CdS for UV-Vis-driven H2 evolution reaction (HER), as confirmed by PL and photoelectrochemical measurements. More importantly, the Co-S bonds at the interface demonstrated by FTIR, Raman (mapping), XPS and density functional theory (DFT) calculations can act as “bridge” for charge transfer, thereby enhancing the full spectrum-driven H2 evolution. To our best knowledge, this is a rare research on full spectrum-driven photocatalytic HER without noble metal.

Two homologous 2-oxoglutarate-dependent (ODD) nonheme enzymes thebaine 6-O-demethylase (T6ODM) and codeine-3-O-demethylase (CODM), are involved in the morphine biosynthesis pathway from thebaine, catalyzing the O-demethylation reaction with precise regioselectivity at C6 and C3 positions of thebaine respectively. We investigated the origin of the regioselectivity of these enzymes by combined molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations and found that Thebaine binds at the two distinct sites of T6ODM and CODM, which determines the regioselectivity of the enzymes. A remarkable oxo rotation is observed in the decarboxylation process. Starting from the closed pentacoordinate configuration, the C-terminal lid adopts an open conformation in the octahedral Fe(IV) = O complex to facilitate the subsequent demethylation. Phe241 and Phe311 stabilize the substrate in the binding pocket, while Arg219 acts as a gatekeeper residue to stabilize the substrate. Our results unravel the regioselectivity in 2-OG dependent nonheme enzymes and may shed light for exploring the substrate scope of these enzymes and developing novel biotechnology for morphine biosynthesis.

A quantitative structure–property relationship (QSPR) study was performed for predicting the hydrophobicity of Pt(IV) complexes. Two four-parameter equations, one based solely on structural descriptors derived from electrostatic potentials (ESPs) on molecular surface, and the other integrated ESP descriptors with molecular surface area (AS), were firstly constructed. Mechanistic interpretations of the structural descriptors introduced were elucidated in terms of solute-solvent intermolecular interactions. Subsequently, several up-to-date modeling techniques, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. The predictive performances of the four different nonlinear modeling methods follow the order of LSSVM≈GP > RF > SVM. The pure-ESP-based models are generally inferior to the AS-integrated ones. Comparisons with previous results were made.

The substitution of a portion of methylammonium (MA) for guanidinium (GA) has been verified to be able to enhance the stability of MA-based devices. However, high-dose guanidinium cation will introduce localized distortions to the perovskite lattice structure and destroy the microstructure of the perovskite films, impairing the stability and reproducibility of perovskite solar cells (PSCs) eventually. Herein, for the first time, the NH4Br-assisted all-atmospheric two-step process is adopted to fabricate GA-rich (20%) perovskite films. The NH4Br induces the formation of the intermediate phase NH4PbI3 and alleviates the disorder of the octahedron caused by the big GA. Consequently, the modified perovskite film shows increased tolerance for the roughness fluctuation and reduced risk of forming voids and pinholes. The fabricated compact GA-rich perovskite films behave extremely well in photovoltaic performance when assembled as carbon-based perovskite solar cells, delivering a high power conversion efficiency (PCE) of 16.19% and stability against moisture and sunlight. Especially, the unencapsulated devices in ambient air sustain 95.1%, 91.8%, and 95.7% of their initial PCEs after 2400 h of storage, after 1000 h of 65 °C heat environment, and after 800 h of sunlight illumination, respectively.

The site-selective C-H oxidation of terpenoids by P450 attracts great attention because of their wide range of biological activities. However, the binding and catalytic mechanism of P450 for the hydroxylation of complex terpenoid substrates remains elusive, which has limited the rational engineering of P450 as a biocatalyst for terpenoid biosynthesis. Here, we studied the origin of the selectivity and reactivity of P450BM3 in the hydroxylation of terpenoids by combining molecular dynamics simulations and QM/MM calculations, using artemisinin as a model compound. We found that the conformational change of the β1 sheet at the substrate entrance and the displacement of the β' helix were critical for reshaping the binding pocket to modulate substrate entrance and positioning the C-H to be activated toward the oxidative species of P450 for the subsequent hydrogen abstraction, the rate-determining step of hydroxylation. There is a distinct linear correlation between activation barriers and reaction coordinates, indicating that reaction coordinates can be used as a facile descriptor for predicting the reactivity of P450BM3. These findings would provide valuable guidance for predicting the selectivity and reactivity of P450BM3 for the selective hydroxylation of non-native terpenoid substrates so as to prioritize the rationally designed enzymes for terpenoid biosynthesis.

The localization of photogenerated electrons in photovoltaic and photocatalytic materials is crucial for reducing the electron-hole recombination rate. Here, the photogenerated electron localization is systematically investigated on the CH

The mutagenesis of a "second sphere" switch residue of CHMOAcineto could control its enantio- and regiopreference. Replacing phenylalanine (F) at position 277 of CHMOAcineto into larger tryptophan (W) enabled a significant enhancement of enantio- or regioselectivity toward structurally diverse substrates, moreover, a complete reversal of enantio- or regiopreference was realized by mutating F277 into a range of smaller amino acids (A/C/D/E/G/H/I/K/L/M/N/P/Q/R/S/T/V).

Mevalonate Kinase (MVK) catalyses the ATP-Mg2+ mediated phosphate transfer of mevalonate to produce mevalonate 5-phosphate and is a key kinase in the mevalonate pathway in the biosynthesis of isopentenyl diphosphate, the precursor of isoprenoid-based biofuels. However, the crystal structure in complex with the native substrate mevalonate, ATP and Mg2+ has not been resolved, which has limited the understanding of its reaction mechanism and therefore its application in the production of isoprenoid-based biofuels. Here using molecular docking, molecular dynamic (MD) simulations and a hybrid QM/MM study, we revisited the location of Mg2+ resolved in the crystal structure of MVK and determined a catalytically competent MVK structure in complex with the native substrate mevalonate and ATP. We demonstrated that significant conformational change on a flexilble loop connecting the α6 and α7 helix is induced by the substrate binding. Further, we found that Asp204 is coordinated to the Mg2+ ion. Arg241 plays a crucial role in organizing the triphosphoryl tail of ATP for in-line phosphate transfer and stabilizing the negative charge that accumulates at the β,γ-bridging oxygen of ATP upon bond cleavage. Remarkably, we revealed that the phosphorylation of mevalonate catalyzed by MVK occurs via a direct phosphorylation mechanism, instead of the conventionally postulated catalytic base mechanism. The catalytically competent complex structure of MVK as well as the mechanism of reaction will pave the way for the rational engineering of MVK to exploit its applications in the production of biofuels.

The hallmark reaction of P450 monooxygenase involves activation of C–H bond and the production of a hydroxyl. P450s tailoring natural product could further oxidize the hydroxyl to carboxylic acid. However, heterogeneously expressed plant P450s display poor chemo- and regioselectivity in microbes, restricting the efficient biosynthesis of related natural products. CYP72A63 is a P450 enzyme previously used for the biosynthesis of glycyrrhetinic acid, and its poor selectivity resulted in oxidation of 11-oxo-β-amyrin to a mixture of rare licorice triterpenoids (glycyrrhetol, glycyrrhetaldehyde, glycyrrhetinic acid, and 29-OH-11-oxo-β-amyrin). In this study, we have identified key residues, which influence the enzyme–substrate hydrophobic interaction, in controlling the chemo- and regioselectivity of the enzyme and engineered the enzyme toward selectivity oxidation to hydroxyl and carboxylic acid. Moreover, tuning the redox partner of the P450 leads to selective production of glycyrrhetaldehyde, a good starting point for further modification. In this study, controlling the catalytic property of plant P450s prove to be of great use in the synthesis of desired licorice triterpenoids, which can be used in biosynthesis of other terpenoid natural products.

Effective novel peptide inhibitors which targeted the domain III of the dengue envelope (E) protein by blocking dengue virus (DENV) entry into target cells, were identified. The binding affinities of these peptides towards E-protein were evaluated by using a combination of docking and explicit solvent molecular dynamics (MD) simulation methods. The interactions of these complexes were further investigated by using the Molecular Mechanics-Poisson Boltzmann Surface Area (MMPBSA) and Molecular Mechanics Generalized Born Surface Area (MMGBSA) methods. Free energy calculations of the peptides interacting with the E-protein demonstrated that van der Waals (vdW) and electrostatic interactions were the main driving forces stabilizing the complexes. Interestingly, calculated binding free energies showed good agreement with the experimental dissociation constant (Kd) values. Our results also demonstrated that specific residues might play a crucial role in the effective binding interactions. Thus, this study has demonstrated that a combination of docking and molecular dynamics simulations can accelerate the identification process of peptides as potential inhibitors of dengue virus entry into host cells.

Mevalonate diphosphate decarboxylase (MDD) catalyses a crucial step of the mevalonate pathway via Mg2+-ATP-dependent phosphorylation and decarboxylation reactions to ultimately produce isopentenyl diphosphate, the precursor of isoprenoids, which is essential to bacterial functions and provides ideal building blocks for the biosynthesis of isopentenols. However, the metal ion(s) in MDD has not been unambiguously resolved, which limits the understanding of the catalytic mechanism and the exploitation of enzymes for the development of antibacterial therapies or the mevalonate metabolic pathway for the biosynthesis of biofuels. Here by analogizing structurally related kinases and molecular dynamics simulations, we constructed a model of the MDD-substrate-ATP-Mg2+ complex and proposed that MDD requires two Mg2+ ions for maintaining a catalytically active conformation. Subsequent QM/MM studies indicate that MDD catalyses the phosphorylation of its substrate mevalonate diphosphate (MVAPP) via a direct phosphorylation reaction, instead of the previously assumed catalytic base mechanism. The results here would shed light on the active conformation of MDD-related enzymes and their catalytic mechanisms and therefore be useful for developing novel antimicrobial therapies or reconstructing mevalonate metabolic pathways for the biosynthesis of biofuels.

Enzymatic Baeyer‐Villiger oxidation provides a promising green route utilizing molecular oxygen as the oxidant to produce chiral lactones. Wild‐type (WT) CHMOAcineto leads to enantioselectivity up to 99 % ee (S) in the synthesis of substituted ϵ‐caprolactones. To reverse the inherent enantiopreference of CHMOAcineto toward an array of cyclohexanones with various chain length, we herein reshaped the binding pocket with a minimal number of mutations by a rational design strategy combining “size‐probes” with in silico study, which drastically reduces the screening effort. By probing the binding pocket of variants with different‐sized 4‐substituted cyclohexanones substrates, single, double and triple mutants were identified as the best mutants providing highly reversed enantioselectivity for these probing molecules, respectively. The successful demonstration of the strategy combining “size‐probes” with in silico study in the protein engineering of CHMOAcineto may provide a valuable guidance for facile engineering other BVMOs with customized enantiopreference for the same classified substrates with their substituents on the chiral or prochiral central atom.

Histone demethylases (KDMs) catalyze histone lysine demethylation, an important epigenetic process that controls gene expression in eukaryotes, and represent important cancer drug targets for cancer treatment. Demethylation of histone is comprised of sequential reaction steps including oxygen activation, decarboxylation, and demethylation. The initial oxygen binding and activation steps have been studied. However, the information on the complete catalytic reaction cycle is limited, which has impeded the structure-based design of inhibitors targeting KDMs. Here we report the mechanism of the complete reaction steps catalyzed by a representative nonheme iron αKG-dependent KDM, PHF8 using QM/MM approaches. The atomic-level understanding on the complete reaction mechanism of PHF8 would shed light on the structure-based design of selective inhibitors targeting KDMs to intervene in cancer epigenetics.

Lipoproteins are essential for bacterial survival. Bacterial lipoprotein biosynthesis is accomplished by sequential modification by three enzymes in the inner membrane, all of which are emerging antimicrobial targets. The X-ray crystal structure of prolipoprotein diacylglyceryl transferase (Lgt) and apolipoprotein N-acyl transferase (Lnt) has been reported. However, the mechanisms of the posttranslational modification catalyzed by these enzymes have not been understood. Here, we studied the mechanism of thetransacylation reaction catalyzed by Lgt, the first enzyme for lipoprotein modification using molecular docking, molecular dynamics, and quantum mechanics/molecular mechanics (QM/MM) calculations. Our results suggest that Arg143, Arg239, and Glu202 play a critical role in stabilizing the glycerol1-phosphate head group and activating the glycerol C3−O ester bond of the phosphatidylglycerol (PG) substrate. With PG binding, the opening of the L6−7 loop mediated by the highly conserved Arg236 residue as a gatekeeper is observed, which facilitates the release of the modified lipoprotein product, as well as the entry of another PG substrate. Further QM/MM studies revealed that His103 acts as a catalytic base to abstract a proton from the cysteine residue of the preproliprotein, initiating the diacylglyceryl transfer from PG to preprolipoprotein. This is the first study on the mechanism of lipoprotein modification catalyzed by a post-translocational processing enzyme. The transacylation mechanism of Lgt would shed light on the development of novel antimicrobial therapies targeting the challenging enzymes involved in the post-translocationalmodification pathway of lipoproteins.

Histone Lysine Specific Demethylase 1 (LSD1) is overexpressed in many cancers and become a new target for anticancer drugs. In recent years, the small molecule inhibitors with various structures targeting LSD1 have been reported. Here we report the binding interaction modes of a series of thieno[3,2-b]pyrrole-5-carboxamides LSD1 inhibitors using molecular docking, three dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q2=0.783, r2=0.944, r2pred=0.851) and Comparative molecular similarity indices analysis (CoMSIA q2=0.728, r2=0.982, r2pred=0.814) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 8 novel small molecules were designed in silico, among which compounds D4, D5 and D8 with high predictive activity were subjected to further molecular dynamics simulations (MD), and their possible binding modes were explored. It was found that Asn535 plays a crucial role in stabilizing the inhibitors. Furthermore, the ADME and bioavailability prediction for D4, D5 and D8 were carried out. The results would provide valuable guidance for designing new reversible LSD1 inhibitors in the future.

Galactokinase catalyses the ATP-dependent phosphorylation of galactose and structurally related sugars. The enzyme has attracted interest as a potential biocatalyst for the production of sugar 1-phosphates and several attempts have been made to broaden its specificity. In general, bacterial galactokinases have wider substrate ranges than mammalian ones. The enzymes from Escherichia coli and Lactococcus lactis have received particular attention and a number of variants with increased promiscuity have been identified. Here, we present a molecular dynamics study designed to investigate the molecular causes of the wider substrate ranges of these enzymes and their variants with particular reference to protein mobility. Some regions close to the active site of the enzyme have different structures in the bacterial enzymes compared to the human one. Alterations known to increase the substrate range (e.g. Y371H in the E. coli enzyme), tend to alter the conformation of a key α-helical region (residues 216–232 in the E. coli enzyme). The equivalent helix in the human enzyme has previously been predicted to be altered in variants which affect catalytic activity or protein stability. This helix appears to be a key region in galactokinases from a range of species and may represent an interesting target for future attempts to broaden the specificity of galactokinases.

Enzymatic stereodivergent synthesis to access all possible product stereoisomers bearing multiple stereocenters is relatively undeveloped, although enzymes are being increasingly used in both academic and industrial areas. When two stereocenters and thus four stereoisomeric products are involved, obtaining stereodivergent enzyme mutants for individually accessing all four stereoisomers would be ideal. Although significant success has been achieved in directed evolution of enzymes in general, stereodivergent engineering of one enzyme into four highly stereocomplementary variants for obtaining the full complement of stereoisomers bearing multiple stereocenters remains a challenge. Using Candida antarctica lipase B (CALB) as a model, we report the protein engineering of this enzyme into four highly stereocomplementary variants needed for obtaining all four stereoisomers in transesterification reactions between racemic acids and racemic alcohols in organic solvents. By generating and screening less than 25 variants of each isomer, we achieved >90% selectivity for all of the four possible stereoisomers in the model reaction. This difficult feat was accomplished by developing a strategy dubbed "focused rational iterative site-specific mutagenesis" (FRISM) at sites lining the enzyme's binding pocket. The accumulation of single mutations by iterative site-specific mutagenesis using a restricted set of rationally chosen amino acids allows the formation of ultrasmall mutant libraries requiring minimal screening for stereoselectivity. The crystal structure of all stereodivergent CALB variants, flanked by MD simulations, uncovered the source of selectivity.

In microorganisms and plants, N-acetyl-l-glutamate kinase (NAGK) catalyzes the second step in l-arginine synthesis, the phosphorylation of N-Acetyl-l-glutamate (NAG) to give N-acetyl-l-glutamate-5-phosphate. NAGK is only present in microorganisms and plants but absent in mammals, which makes it an attractive target for antimicrobial or biocidal development. Understanding the substrate binding mode and reaction mechanism of NAGK is crucial for targeting the kinase to develop potential therapies. Here, the substrate binding mode was studied by comparing the conformational change of NAGK in the presence and in the absence of the NAG substrate based on molecular dynamics simulations. We revealed that with substrate binding, the catalytic site of the kinase involving three loops in NAGK exhibits a closed conformation, which is predominantly controlled by an interaction between Arg98 and the α-COO- of NAG. Lys41 is found to guide phosphate transfer through the interactions with the β-,γ-, and γ-phosphate oxygen atoms of adenosine 5'-triphosphate surrounded by two highly conserved glycine residues (Gly44 and Gly76), while Arg98 helps to position the NAG substrate in the catalytic site, which facilitates the phosphate transfer. Furthermore, we elucidated phosphate-transfer reaction mechanism using hybrid density functional theory-based quantum mechanics/molecular mechanics calculations (B97D/AMBER99) and found that the catalysis follows a dissociative mechanism.

Integration of the upconversion effect in perovskite solar cells (PSCs) is a facile approach towards extending the spectral absorption from the visible to the near infrared (NIR) range and reducing the non-absorption loss of solar photons. However, the big challenge for practical application of UCNCs in planar PSCs is the poor compatibility between UCNCs and the perovskite precursor. Herein, we have subtly overcome the tough compatibility issue using a ligand-exchange strategy. For the first time, β-NaYF4:Yb,Er UCNCs have been embedded in situ into a CH3NH3PbI3 layer to fabricate NIR-enabled planar PSCs. The CH3NH3I-capped UCNCs generated from the ligand-exchange were mixed with the perovskite precursor and served as nucleation sites for the UCNC-mediated heteroepitaxial growth of perovskite; moreover, the in situ embedding of UCNCs into the perovskite layer was realized during a spin-coating process. The resulting UCNC-embedded perovskite layer attained a uniform pinhole-free morphology with enlarged crystal grains and enabled NIR absorption. It also contributed to the energy transfer from the UCNCs to the perovskite and electron transport to the collecting electrode surface. The device fabricated using the UCNC-embedded perovskite film achieved an average power-conversion efficiency of 18.60% (19.70% for the best) under AM 1.5G and 0.37% under 980 nm laser, corresponding to 54% and 740-fold increase as compared to that of its counterpart without UCNCs.

Dye-sensitized solar cell (DSSC) is currently a promising technology that makes solar energy efficient and cost-effective to harness. In DSSC, metal-free dyes such as indoline-containing D149 and D205 have been proven to be potential alternatives for traditional metal organic dyes. In this work, a DFT/TDDFT characterization for D149 and D205 was carried out using different functionals, including B3LYP, MPW1K, CAM–B3LYP, and PBE0. Three different conformers for D149 and four different conformers for D205 were identified and calculated in a vacuum. The performance of different functionals on calculating the maximum absorbance of the dyes in a vacuum and five common solvents (acetonitrile, chloroform, ethanol, methanol, and THF) were examined and compared to determine the suitable computational setting for predicting properties of these two dyes. Furthermore, deprotonated D149 and D205 in solvents were also considered, and the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were calculated, which elucidates the substitution effect on the rhodanine ring of D149 and D205 dyes on their efficiency. Finally, D149 and D205 molecules were confirmed to be firmly anchored on ZnO surface by periodic DFT calculations. These results shed light on the design of new, highly efficient metal-free dyes.