On-the-fly kinetic Monte Carlo simulations with neural network potentials for surface diffusion and reaction.

We develop an adaptive scheme in the kinetic Monte Carlo simulations, where the adsorption and activation energies of all elementary steps, including the effects of other adsorbates, are evaluated "on-the-fly" by employing the neural network potentials. The configurations and energies evaluated during the simulations are stored for reuse when the same configurations are sampled in a later step. The present scheme is applied to hydrogen adsorption and diffusion on the Pd(111) and Pt(111) surfaces and the CO oxidation reaction on the Pt(111) surface. The effects of interactions between adsorbates, i.e., adsorbate-adsorbate lateral interactions, are examined in detail by comparing the simulations without considering lateral interactions. This study demonstrates the importance of lateral interactions in surface diffusion and reactions and the potential of our scheme for applications in a wide variety of heterogeneous catalytic reactions.

Long-range proton and hydroxide ion transfer dynamics at the water/CeO2 interface in the nanosecond regime: reactive molecular dynamics simulations and kinetic analysis.

The structural properties, dynamical behaviors, and ion transport phenomena at the interface between water and cerium oxide are investigated by reactive molecular dynamics (MD) simulations employing neural network potentials (NNPs). The NNPs are trained to reproduce density functional theory (DFT) results, and DFT-based MD (DFT-MD) simulations with enhanced sampling techniques and refinement schemes are employed to efficiently and systematically acquire training data that include diverse hydrogen-bonding configurations caused by proton hopping events. The water interfaces with two low-index surfaces of (111) and (110) are explored with these NNPs, and the structure and long-range proton and hydroxide ion transfer dynamics are examined with unprecedented system sizes and long simulation times. Various types of proton hopping events at the interface are categorized and analyzed in detail. Furthermore, in order to decipher the proton and hydroxide ion transport phenomena along the surface, a counting analysis based on the semi-Markov process is formulated and applied to the MD trajectories to obtain reaction rates by considering the transport as stochastic jump processes. Through this model, the coupling between hopping events, vibrational motions, and hydrogen bond networks at the interface are quantitatively examined, and the high activity and ion transport phenomena at the water/CeO2 interface are unequivocally revealed in the nanosecond regime.

AJICAP-M: Traceless Affinity Peptide Mediated Conjugation Technology for Site-Selective Antibody-Drug Conjugate Synthesis.

A traceless site-selective conjugation method, "AJICAP-M", was developed for native antibodies at sites using Fc-affinity peptides, focusing on Lys248 or Lys288. It produces antibody-drug conjugates (ADCs) with consistent drug-to-antibody ratios, enhanced stability, and simplified manufacturing. Comparative in vivo assessment demonstrated AJICAP-M's superior stability over traditional ADCs. This technology has been successfully applied to continuous-flow manufacturing, marking the first achievement in site-selective ADC production. This manuscript outlines AJICAP-M's methodology and its effectiveness in ADC production.

Synthesis and Structural Analysis of High-Silica ERI Zeolite with Spatially-Biased Al Distribution as a Promising NH3-SCR Catalyst.

Erionite (ERI) zeolite has recently attracted considerable attention for its application prospect in the selective catalytic reduction of NOx with NH3 (NH3-SCR), provided that the high-silica (Si/Al > 5.5) analog with improved hydrothermal stability can be facilely synthesized. In this work, ERI zeolites with different Si/Al ratios (4.6, 6.4, and 9.1) are synthesized through an ultrafast route, and in particular, a high-silica ERI zeolite with a Si/Al ratio of 9.1 is obtained by using faujasite (FAU) as a starting material. The solid-state 29Si MAS NMR spectroscopic study in combination with a computational simulation allows for figuring out the atomic configurations of the Al species in the three ERI zeolites. It is revealed that the ERI zeolite with the highest Si/Al ratio (ERI-9.1, where the number indicates the Si/Al ratio) exhibits a biased Al occupancy at T1 site, which is possibly due to the presence of a higher fraction of the residual potassium cations in the can cages. In contrast, the Al siting in ERI-4.6 and ERI-6.4 proves to be relatively random.

Catalytic ammonia synthesis on HY-zeolite-supported angstrom-size molybdenum cluster.

The development of new catalysts with high N2 activation ability is an effective approach for low-temperature ammonia synthesis. Herein, we report a novel angstrom-size molybdenum metal cluster catalyst for efficient ammonia synthesis. This catalyst is prepared by the impregnation of a molybdenum halide cluster complex with an octahedral Mo6 metal core on HY zeolite, followed by the removal of all the halide ligands by activation with hydrogen. In this activation, the size of the Mo6 cluster (ca. 7 Å) is almost retained. The resulting angstrom-size cluster shows catalytic activity for ammonia synthesis from N2 and H2, and the reaction proceeds continuously even at 200 °C under 5.0 MPa. DFT calculations suggest that N[triple bond, length as m-dash]N bond cleavage is promoted by the cooperation of the multiple molybdenum sites.

Dimethyl carbonate synthesis from CO2 and methanol over CeO2: elucidating the surface intermediates and oxygen vacancy-assisted reaction mechanism.

Surface intermediate species and oxygen vacancy-assisted mechanism over CeO2 catalyst in the direct dimethyl carbonate (DMC) synthesis from carbon dioxide and methanol are suggested by means of transient spectroscopic methodologies in conjunction with multivariate spectral analysis. How the two reactants, i.e. CO2 and methanol, interact with the CeO2 surface and how they form decisive surface intermediates leading to DMC are unraveled by DFT-based molecular dynamics simulation by precise statistical sampling of various configurations of surface states and intermediates. The atomistic simulations and uncovered stability of different intermediate states perfectly explain the unique DMC formation profile experimentally observed upon transient operations, strongly supporting the proposed oxygen vacancy-assisted reaction mechanism.

Comparative Study between 2-Furonitrile and 2-Cyanopyridine as Dehydrants in Direct Synthesis of Dialkyl Carbonates from CO2 and Alcohols over Cerium Oxide Catalyst.

The shift of equilibrium by removing water with nitrile dehydrants is crucial for CeO2 -catalyzed synthesis of dialkyl carbonates from CO2 and alcohols. Two nitriles - 2-cyanopyridine and 2-furonitrile - were previously found as effective dehydrants, yet their detailed comparison as well as exploration of potential of 2-furonitrile remain insufficient. Herein, the performance of 2-cyanopyridine and 2-furonitrile was compared in the synthesis of various dialkyl carbonates. 2-furonitrile was found to be superior to 2-cyanopyridine in the synthesis of dialkyl carbonates from CO2 and bulky or long-chain (≥C3) alcohols. Namely, the yield of diisopropyl carbonate (up to 50 %) achieved using CeO2 and 2-furonitrile is comparable to or even higher than previously reported ones. Meanwhile, 2-cyanopyridine acted as a better dehydrant than 2-furonitrile in the synthesis of dimethyl carbonate and diethyl carbonate. The adsorption experiments and density functional theory calculations have indicated that the better performance of 2-furonitrile compared to 2-cyanopyridine in the synthesis of dialkyl carbonates from bulky or long-chain alcohols is due to the weaker interaction of 2-furonitrile with the CeO2 surface. Such weak interaction of 2-furonitrile offers a larger reaction field on the catalyst surface for both CO2 and alcohols.

Analysis of Al site-directing ability of organic structure-directing agents in FER and CHA zeolites: a computational exploration of energetic preferences.

This study explores the control of Al location in zeolites by organic structure-directing agents (OSDAs) using atomistic simulations. We examine several zeolite-OSDA complexes to quantify the Al site-directing ability. The results show that OSDAs induce different energetic preferences to direct Al at certain locations. In particular, these effects can be enhanced by OSDAs with N-H moieties. Our findings will be useful for the development of novel OSDAs that can modulate Al site-directing properties.

AJICAP Second Generation: Improved Chemical Site-Specific Conjugation Technology for Antibody-Drug Conjugate Production.

The site-directed chemical conjugation of antibodies remains an area of great interest and active efforts within the antibody-drug conjugate (ADC) community. We previously reported a unique site modification using a class of immunoglobulin-G (IgG) Fc-affinity reagents to establish a versatile, streamlined, and site-selective conjugation of native antibodies to enhance the therapeutic index of the resultant ADCs. This methodology, termed "AJICAP", successfully modified Lys248 of native antibodies to produce site-specific ADC with a wider therapeutic index than the Food and Drug Administration-approved ADC, Kadcyla. However, the long reaction sequences, including the reduction-oxidation (redox) treatment, increased the aggregation level. In this manuscript, we aimed to present an updated Fc-affinity-mediated site-specific conjugation technology named "AJICAP second generation" without redox treatment utilizing a "one-pot" antibody modification reaction. The stability of Fc affinity reagents was improved owing to structural optimization, enabling the production of various ADCs without aggregation. In addition to Lys248 conjugation, Lys288 conjugated ADCs with homogeneous drug-to-antibody ratio of 2 were produced using different Fc affinity peptide reagent possessing a proper spacer linkage. These two conjugation technologies were used to produce over 20 ADCs from several combinations of antibodies and drug linkers. The in vivo profile of Lys248 and Lys288 conjugated ADCs was also compared. Furthermore, nontraditional ADC production, such as antibody-protein conjugates and antibody-oligonucleotide conjugates, were achieved. These results strongly indicate that this Fc affinity conjugation approach is a promising strategy for manufacturing site-specific antibody conjugates without antibody engineering.

Biological Evaluation of Maytansinoid-Based Site-Specific Antibody-Drug Conjugate Produced by Fully Chemical Conjugation Approach: AJICAP®.

BACKGROUND: Trastuzumab-emtansine (T-DM1, commercial name: Kadcyla) is well-known antibody-drug conjugate (ADC) and was first approved for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This molecular format consisting of trastuzumab and maytansinoid payload (emtansine) is very simple, however, T-DM1 has wide heterogeneity due to non-specific conjugation, lowering its therapeutic index (TI). METHODS: To overcome this issue during the chemical modification of the random conjugation approach to generate T-DM1, we developed a novel chemical conjugation technology termed "AJICAP®" for modification of antibodies in site-specific manner by IgG Fc-affinity peptide based reagents. RESULTS: In this study, we compared site-specific maytansinoid-based ADCs synthesized by AJICAP and T-DM1 in rat safety studies. The results indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index compared with that of commercially available T-DM1. Gram scale preparation of this AJICAP-ADC and the initial stability study are also described. CONCLUSIONS: Trastuzumab-AJICAP-maytansinoid produced by this unique chemical conjugation methodology showed higher stability and tolerability than commercially available T-DM1.

Analytical Chemistry of Impurities in Amino Acids Used as Nutrients: Recommendations for Regulatory Risk Management.

Proteinogenic amino acids are natural nutrients ingested daily from standard foods. Commercially manufactured amino acids are added to a wide range of nutritional products, including dietary supplements and regular foods. Currently, the regulatory risk management of amino acids is conducted by means of setting daily maximum limits of intake. However, there have been no reported adverse effects of amino acid overdosing, while impurities in low-quality amino acids have been identified as causative agents in several health hazard events. This paper reviews the analytical chemistry of impurities in amino acids and highlights major variations in the purity of commercial products. Furthermore, it examines the international standards and global regulatory risk assessment of amino acids utilized in dietary supplements and foods, recommending (1) further research on analytical methods that can comprehensively separate impurities in amino acids, and (2) re-focusing on the regulatory risk management of amino acids to the analytical chemistry of impurities.

Simultaneous quantification of oligo-nucleic acids and a ferritin nanocage by size-exclusion chromatography hyphenated to inductively coupled plasma mass spectrometry for developing drug delivery systems.

An analytical methodology, which can quantify nucleic acids, ferritin nanocages, and their complexes in a single injection, was established by means of size-exclusion chromatography hyphenated with inductively coupled plasma mass spectrometry (SEC-ICP-MS). In this study, several oligo-nucleic acids and ferritin (a human-derived cage-shaped protein) were used as model compounds of nucleic acid drugs (NAD) and drug delivery system (DDS) carriers, respectively. A fraction based on the nucleic acid-ferritin complex was completely distinguished from one based on free nucleic acids by SEC separation. The nucleic acids and ferritin were quantified based on the number of phosphorus and sulfur atoms, respectively. The quantification was carried out by an external calibration method using a series of elemental standard solutions without preparing designated standard materials for each drug candidate. The analytical performance, including sensitivity and accuracy, was evaluated to be appropriate for evaluating the medicines already launched in the market. As demonstrated in the latter part of this study, the encapsulation mechanism is possibly regulated by not only the averaged molecular size of nucleic acids but also the surface charge related to the number of (deoxy-) ribonucleotides. We believe that the methodology presented in this study has the potential to accelerate the development of new modalities based on NAD-DDS to realize therapies in the future.

Deoxydehydration of Biomass-Derived Polyols Over Silver-Modified Ceria-Supported Rhenium Catalyst with Molecular Hydrogen.

Olefin production from polyols via deoxydehydration (DODH) was carried out over Ag-modified CeO2 -supported heterogeneous Re catalysts with H2 as a reducing agent. Both high DODH activity and low hydrogenation ability for C=C bonds were observed in the reaction of erythritol, giving a 1,3-butadiene yield of up to 90 % under "solvent-free" conditions. This catalyst is applicable to other substrates such as methyl glycosides (methyl α-fucopyranoside: 91 % yield of DODH product; methyl ß-ribofuranoside: 88 % yield), which were difficult to be converted to the DODH products over the DODH catalysts reported previously. ReOx -Ag/CeO2 was reused 3 times without a decrease of activity or selectivity after calcination as regeneration. Although the transmission electron microscopy energy-dispersive X-ray spectroscopy and X-ray absorption fine structure analyses showed that Re species were highly dispersed and Ag was present as metal particles with various sizes from well-dispersed species (<1 nm) to around 5 nm particles, the catalysts prepared from size-controlled Ag nanoparticles showed similar performance, indicating that the catalytic performance is insensitive to the Ag particle size.

Collective bath coordinate mapping of "hierarchy" in hierarchical equations of motion.

The theory of hierarchical equations of motion (HEOM) is one of the standard methods to give exact evaluations of the dynamics as coupled to harmonic oscillator environments. However, the theory is numerically demanding due to its hierarchy, which is the set of auxiliary elements introduced to capture the non-Markovian and non-perturbative effects of environments. When system-bath coupling becomes relatively strong, the required computational resources and precision move beyond the regime that can be currently handled. This article presents a new representation of HEOM theory in which the hierarchy is mapped into a continuous space of a collective bath coordinate and several auxiliary coordinates as the form of the quantum Fokker-Planck equation. This representation gives a rigorous time evolution of the bath coordinate distribution and is more stable and efficient than the original HEOM theory, particularly when there is a strong system-bath coupling. We demonstrate the suitability of this approach to treat vibronic system models coupled to environments.

Detection of impurities in dietary supplements containing L-tryptophan.

Impurities in nine dietary supplements containing L-tryptophan were evaluated using an HPLC methodology. In five tested products, the total impurities were higher than the thresholds described in the Food Chemical Codex or implemented in the EU for pharmaceutical grade L-tryptophan. In addition, liquid chromatography-mass spectrometry was used to specifically test for the presence of 1,1'-ethylidenebis-L-tryptophan (EBT). None of the tested products contained detectable amounts of EBT. High amounts of unidentified impurities in some dietary supplements point to potential health risks.

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody-Drug Conjugates.

To overcome a lack of selectivity during the chemical modification of native non-engineered antibodies, we have developed a technology platform termed "AJICAP" for the site-specific chemical conjugation of antibodies through the use of a class of IgG Fc-affinity reagents. To date, a limited number of antibody-drug conjugates (ADCs) have been synthesized via this approach, and no toxicological study was reported. Herein, we describe the compatibility and robustness of AJICAP technology, which enabled the synthesis of a wide variety of ADCs. A stability assessment of a thiol-modified antibody synthesized by AJICAP technology indicated no appreciable increase in aggregation or decomposition upon prolonged storage, indicating that the unexpectedly stable thiol intermediate has a great potential intermediate for payload or linker screening or large-scale manufacturing. Payload conjugation with this stable thiol intermediate generated several AJICAP-ADCs. In vivo xenograft studies indicated that the AJICAP-ADCs displayed significant tumor inhibition comparable to benchmark ADC Kadcyla. Furthermore, a rat pharmacokinetic analysis and toxicology study indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index, compared with stochastic conjugation technology. This is the first report of the therapeutic index estimation of site-specific ADCs produced by utilizing Fc affinity reagent conjugation. The described site-specific conjugation technology is a powerful platform to enable next-generation ADCs through reduced heterogeneity and enhanced therapeutic index.

Catalytic Mechanism of Liquid-Metal Indium for Direct Dehydrogenative Conversion of Methane to Higher Hydrocarbons.

There is a great interest in direct conversion of methane to valuable chemicals. Recently, we reported that silica-supported liquid-metal indium catalysts (In/SiO2) were effective for direct dehydrogenative conversion of methane to higher hydrocarbons. However, the catalytic mechanism of liquid-metal indium has not been clear. Here, we show the catalytic mechanism of the In/SiO2 catalyst in terms of both experiments and calculations in detail. Kinetic studies clearly show that liquid-metal indium activates a C-H bond of methane and converts methane to ethane. The apparent activation energy of the In/SiO2 catalyst is 170 kJ mol-1, which is much lower than that of SiO2, 365 kJ mol-1. Temperature-programmed reactions in CH4, C2H6, and C2H4 and reactivity of C2H6 for the In/SiO2 catalyst indicate that indium selectively activates methane among hydrocarbons. In addition, density functional theory calculations and first-principles molecular dynamics calculations were performed to evaluate activation free energy for methane activation, its reverse reaction, CH3-CH3 coupling via Langmuir-Hinshelwood (LH) and Eley-Rideal mechanisms, and other side reactions. A qualitative level of interpretation is as follows. CH3-In and H-In species form after the activation of methane. The CH3-In species wander on liquid-metal indium surfaces and couple each other with ethane via the LH mechanism. The solubility of H species into the bulk phase of In is important to enhance the coupling of CH3-In species to C2H6 by decreasing the formation of CH4 though the coupling of CH3-In species and H-In species. Results of isotope experiments by combinations of CD4, CH4, D2, and H2 corresponded to the LH mechanism.

Extending nudged elastic band method to reaction pathways involving multiple spin states.

There are diverse reactions including spin-state crossing, especially the reactions catalyzed by transition metal compounds. To figure out the mechanisms of such reactions, the discussion of minimum energy intersystem crossing (MEISC) points cannot be avoided. These points may be the bottleneck of the reaction or inversely accelerate the reactions by providing a better pathway. It is of great importance to reveal their role in the reactions by computationally locating the position of the MEISC points together with the reaction pathway. However, providing a proper initial guess for the structure of the MEISC point is not as easy as that of the transition state. In this work, we extended the nudged elastic band (NEB) method for multiple spin systems, which is named the multiple spin-state NEB method, and it is successfully applied to find the MEISC points while optimizing the reaction pathway. For more precisely locating the MEISC point, a revised approach was adopted. Meanwhile, our examples also suggest that special attention should be paid to the criterion to define an image optimized as the MEISC point.

Development of a 1,3a,6a-triazapentalene derivative as a compact and thiol-specific fluorescent labeling reagent.

For the fluorescence imaging of biologically active small compounds, the development of compact fluorophores that do not perturb bioactivity is required. Here we report a compact derivative of fluorescent 1,3a,6a-triazapentalenes, 2-isobutenylcarbonyl-1,3a,6a-triazapentalene (TAP-VK1), as a fluorescent labeling reagent. The reaction of TAP-VK1 with various aliphatic thiols proceeds smoothly to afford the corresponding 1,4-adducts in high yields, and nucleophiles other than thiols do not react. After the addition of thiol groups in dichloromethane, the emission maximum of TAP-VK1 shifts to a shorter wavelength and the fluorescence intensity is substantially increased. The utility of TAP-VK1 as a compact fluorescent labeling reagent is clearly demonstrated by the labeling of Captopril, which is a small molecular drug for hypertension. The successful imaging of Captopril, one of the most compact drugs, in this study demonstrates the usefulness of compact fluorophores for mechanistic studies.

Distinct ionic adsorption sites in defective Prussian blue: a 3D-RISM study.

Ferric hexacyanoferrate (FeHCF) or Prussian blue (PB) exhibits selective alkali ion adsorption and has great potential for use in various applications. In the present work, alkali ion (Li+, Na+, K+, and Cs+) and water configurations in defective PB (d-PB) were studied by using the statistical mechanics of molecular liquids. The three-dimensional (3D) distribution functions of the ions and water were determined by solving the 3D-reference interaction site model (RISM) equation of systems of a unit lattice of d-PB in electrolyte solutions, i.e., LiCl, NaCl, KCl, and CsCl. The results show the difference in the ion-water configurations and distributions between small (Li+ and Na+) and large ions (K+ and Cs+). The adsorption sites of Li+ and Na+ are located off-center and lie on the diagonal axis. By contrast, the larger ions, K+ and Cs+, are adsorbed at the center of the unit cell. The degree of dehydration due to the adsorption of alkali ions indicates that there was no water exchange during Li+ and Na+ adsorption, whereas two and three water molecules were removed after adsorption of K+ or Cs+ in the unit cell.