Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

A General Model of Impact Sensitivity for Nitrogen-Rich Energetic Materials: A Combined Incremental Theory and Genetic Function Approximation Study.

In this paper, we report the first example of impact sensitivity prediction based on the genetic function approximation (GFA) as a regression method. The prediction is applicable for a wide variety of chemical families, which include nitro compounds, peroxides, nitrogen-rich salts, heterocycles, etc. Within this work, we have obtained 7 empirical models (with 27-32 basis functions), which all provide 0.80≤R2≤0.83 and 7.2 J≤RMSE≤7.8 J (for 450 training set compounds) and 0.64≤R2≤0.70 and 11.2 J≤RMSE≤12.4 J (for 170 test set compounds). The models were developed using Friedman Lack-of-Fit as a scoring function, which allows avoiding an overfitting. All the models have simple descriptors as basis functions and include linear splines. Furthermore, the applied descriptors do not require expensive calculation procedures, namely, non-empirical quantum-chemical calculations, complex iterative procedures, real space electron density analysis, etc. Most descriptors are based on structural and topological analysis and a part of them require very cheap semi-empirical PM6 calculations. The prediction takes a few minutes as an average, and most of the time is for the structure preparation and manual calculation of the descriptor "Increment", which is based on our recent incremental theory.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer.

BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).

FunSPU: A versatile and adaptive multiple functional annotation-based association test of whole-genome sequencing data.

Despite ongoing large-scale population-based whole-genome sequencing (WGS) projects such as the NIH NHLBI TOPMed program and the NHGRI Genome Sequencing Program, WGS-based association analysis of complex traits remains a tremendous challenge due to the large number of rare variants, many of which are non-trait-associated neutral variants. External biological knowledge, such as functional annotations based on the ENCODE, Epigenomics Roadmap and GTEx projects, may be helpful in distinguishing causal rare variants from neutral ones; however, each functional annotation can only provide certain aspects of the biological functions. Our knowledge for selecting informative annotations a priori is limited, and incorporating non-informative annotations will introduce noise and lose power. We propose FunSPU, a versatile and adaptive test that incorporates multiple biological annotations and is adaptive at both the annotation and variant levels and thus maintains high power even in the presence of noninformative annotations. In addition to extensive simulations, we illustrate our proposed test using the TWINSUK cohort (n = 1,752) of UK10K WGS data based on six functional annotations: CADD, RegulomeDB, FunSeq, Funseq2, GERP++, and GenoSkyline. We identified genome-wide significant genetic loci on chromosome 19 near gene TOMM40 and APOC4-APOC2 associated with low-density lipoprotein (LDL), which are replicated in the UK10K ALSPAC cohort (n = 1,497). These replicated LDL-associated loci were missed by existing rare variant association tests that either ignore external biological information or rely on a single source of biological knowledge. We have implemented the proposed test in an R package "FunSPU".

Encapsulating quercetin in cyclodextrin metal-organic frameworks improved its solubility and bioavailability.

BACKGROUND: Quercetin (Que) has many pharmacological activities, such as anticancer, antioxidant, cardiovascular protection, antihypertensive and lipid-lowering activities. However, its poor water solubility greatly limits its application in medicine and food. γ-Cyclodextrin metal-organic frameworks (γ-CD-MOFs) are novel porous carriers for loading functional products. In this study, Que was successfully loaded into γ-CD-MOFs, and the new compound (Que-CD-MOFs) was characterised by X-ray diffraction, infrared spectroscopy, thermogravimetric analysis and scanning electron microscopy. RESULTS: The apparent solubility of Que-CD-MOFs was enhanced by 100-fold compared with that of pure Que. The free radical scavenging ability of the encapsulated Que was significantly improved. The cytotoxicity of Que-CD-MOFs to HK-2 cells was decreased, and their inhibition on HT-29 tumour cells was maintained, as confirmed by CCK-8 assays. Flow cytometry of HT-29 cells showed that Que-CD-MOFs can inhibit G2 phase cells. Based on molecular modelling, Que molecules were preferentially located inside the cavities of γ-CD pairs in γ-CD-MOFs. CONCLUSION: γ-CD-MOFs are promising carriers for bioactive agents in food and pharmaceutical applications. © 2021 Society of Chemical Industry.

An adaptive test for meta-analysis of rare variant association studies.

Single genome-wide studies may be underpowered to detect trait-associated rare variants with moderate or weak effect sizes. As a viable alternative, meta-analysis is widely used to increase power by combining different studies. The power of meta-analysis critically depends on the underlying association patterns and heterogeneity levels, which are unknown and vary from locus to locus. However, existing methods mainly focus on one or only a few combinations of the association pattern and heterogeneity level, thus may lose power in many situations. To address this issue, we propose a general and unified framework by combining a class of tests including and beyond some existing ones, leading to high power across a wide range of scenarios. We demonstrate that the proposed test is more powerful than some existing methods in simulation studies, then show their performance with the NHLBI Exome-Sequencing Project (ESP) data. One gene (B4GALNT2) was found by our proposed test, but not by others, to be statistically significantly associated with plasma triglyceride. The signal was driven by African-ancestry subjects but it was previously reported to be associated with coronary artery disease among European-ancestry subjects. We implemented our method in an R package aSPUmeta, publicly available at https://github.com/ytzhong/metaRV and will be on CRAN soon.

A genetic variant within MDM4 3'UTR miRNA binding site is associated with HPV16-positive tumors and survival of oropharyngeal cancer.

As mouse double minute 4 (MDM4) and HPV16 E6 oncoproteins play important roles in inhibition of p53 activity, a functional polymorphism (rs4245739) in the 3' untranslated regions of MDM4 targeted by microRNA-191 may alter its expression level or functional efficiency, thus affecting tumor status and survival in human papillomavirus (HPV)-positive squamous cell carcinoma of oropharynx (SCCOP). A total of 564 incident SCCOP patients with definitive radiotherapy were included for determination of tumor HPV16 status and genotypes of the polymorphism. Univariate and multivariable Cox models were performed to assess the associations between the polymorphism and outcomes. We found that MDM4 rs4245739 had statistically significant associations with tumor HPV-positivity and survival of SCCOP patients. Patients with AC/CC variant genotypes of MDM4 rs4245739 were approximately 3-fold more likely to be HPV16-positive tumors among SCCOP patients compared with common homozygous AA genotype (adjusted odds ratio = 3.2, 95% confidence interval = 1.9-5.5). Moreover, patients with MDM4 rs4245739 AC/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous AA genotype (all log-rank = P < .05); and these genotypes were significantly associated with an approximately three to four times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Finally, the significant effects of MDM4 rs4245739 polymorphism on survival were found among HPV16-positive SCCOP patients only after the stratified analyses by tumor HPV status. We concluded that MDM4 rs4245739 polymorphism is significantly associated with tumor HPV status and survival of SCCOP, especially in HPV16-positive SCCOP patients treated with definitive radiotherapy; nevertheless, prospective larger studies are warranted.

Structural Rearrangement of Energetic Materials under an External Electric Field: A Case Study of Nitromethane.

As a significant stimulus, the external electric field (EEF) can change the decomposition mechanism and energy release of energetic materials (EMs). Hence, understanding the response of EMs to an EEF is greatly meaningful for their safe usage. Herein, the structural arrangement, a crucial factor in the impact sensitivity and detonation performance of EMs, under the EEF ranging from 0.0 to 0.5 V/Å was investigated via molecular dynamics simulation. Nitromethane (NM) was taken as a case study due to the simple structure. The simulation results show that there exists a critical EEF strength between 0.2 and 0.3 V/Å, which can induce the transition of NM molecules from relatively disordered distribution to solidlike ordered and compacted arrangement with a large density. In this ordered structure, NM dipoles are aligned in a head-to-tail pattern parallel to the EEF direction because of the favored dipole-dipole interactions and weak C-H···O hydrogen bonds. As the EEF strength is enhanced, the potential energy and cohesive energy density of the NM system gradually decrease and increase, respectively, indicative of high thermodynamics stability of ordered arrangement. The results reported here also shed light on the potential of the EEF to induce the nucleation and crystallization to explore new polymorphs of EMs.

Comparison of inorganic chemical compositions of atmospheric TSP, PM10 and PM2.5 in northern and southern Chinese coastal cities.

To compare the inorganic chemical compositions of TSP (total suspended particulate), PM10 (particulate matter with an aerodynamic diameter less than 10µm) and PM2.5 (particulate matter with an aerodynamic diameter less than 2.5µm) in southern and northern cities in China, atmospheric particles were synchronously collected in Dalian (the northern city) and Xiamen (the southern city) in spring and autumn of 2004. The mass concentrations, twenty-three elements and nine soluble ions were assessed. The results show that in Dalian, the mass concentrations of Mg, Al, Ca, Mn and Fe in spring were 4.0-10.1, 2.6-8.0, 4.1-12, 1.2-3.6 and 2.9-7.9 times higher, respectively, than those in Xiamen. The dust storm influence is more obvious in Dalian in spring. However, in Xiamen, heavy metals accounted for 13.9%-17.9% of TSP, while heavy metals contributed to 5.5%-9.3% of TSP in Dalian. These concentrations suggest that heavy metal pollution in Xiamen was more serious. In addition, the concentrations of Na+, Cl-, Ca2+ and Mg2+ were higher in Dalian due to the influence of marine aerosol, construction activities and soil dust. The NO3-/SO42- ratios in Dalian (0.25-0.49) were lower than those in Xiamen (0.51-0.62), indicating that the contributions of vehicle emission to particles in Xiamen were higher. Coefficient of divergence values was higher than 0.40, implying that the inorganic chemical composition profiles for the particles of Dalian and Xiamen were quite different from each other.

How nonspecifically DNA-binding proteins search for the target in crowded environments.

We investigate how a tracer particle searches a target located in DNA modeled by a stiff chain in crowded environments using theoretical analysis and Langevin dynamics simulations. First, we show that the three-dimensional (3D) diffusion coefficient of the tracer only depends on the density of crowders ϕ, while its one-dimensional (1D) diffusion coefficient is affected by not only ϕ but also the nonspecific binding energy ε. With increasing ϕ and ε, no obvious change in the average 3D diffusion time is observed, while the average 1D sliding time apparently increases. We propose theoretically that the 1D sliding of the tracer along the chain could be well captured by the Kramers' law of escaping rather than the Arrhenius law, which is verified directly by the simulations. Finally, the average search time increases monotonously with an increase in ϕ while it has a minimum as a function of ε, which could be understood from the different behaviors of the average number of search rounds with the increasing ϕ or ε. These results provide a deeper understanding of the role of facilitated diffusion in target search of proteins on DNA in vivo.

Increased protein sorption in poly(acrylic acid)-containing films through incorporation of comb-like polymers and film adsorption at low pH and high ionic strength.

In principle, incorporation of comb-like block copolymers in multilayer polyelectrolyte films can both increase film thickness relative to coatings containing linear polymers and provide more swollen films for increased sorption of proteins. In the absence of added salt, alternating adsorption of 5 bilayers of protonated poly(allylamine) (PAH) and comb-like poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) (PHEMA-g-PAA) leads to ∼2-fold thicker coatings than adsorption of PAH and linear PAA, and the difference in the thicknesses of the two coatings increases with the number of bilayers. Moreover, the (PAH/PHEMA-g-PAA)n films sorb 2- to 4-fold more protein than corresponding films prepared with linear PAA, and coatings deposited at pH 3.0 sorb more protein than coatings adsorbed at pH 5.0, 7.0, or 9.0. In fact changes in deposition pH and addition of 0.5 M NaCl to polyelectrolyte adsorption solutions alter protein sorption more dramatically than variations in the constituent polymer architecture. When deposited from 0.5 M NaCl at pH 3.0, both (PAH/PHEMA-g-PAA)5 and (PAH/PAA)5 films increase in thickness more than 400% upon adsorption of lysozyme. These films contain a high concentration of free -COOH groups, and subsequent deprotonation of these groups at neutral pH likely contributes to increased protein binding. Lysozyme sorption stabilizes these films, as without lysozyme films deposited at pH 3.0 from 0.5 M NaCl desorb at neutral pH. Films deposited at pH 9.0 from 0.5 M NaCl are more stable and also bind large amounts of lysozyme. The high binding capacities of these films make them attractive for potential applications in protein isolation or immobilization of enzymes.

Formation of high-capacity protein-adsorbing membranes through simple adsorption of poly(acrylic acid)-containing films at low pH.

Layer-by-layer polyelectrolyte adsorption is a simple, convenient method for introducing ion-exchange sites in porous membranes. This study demonstrates that adsorption of poly(acrylic acid) (PAA)-containing films at pH 3 rather than pH 5 increases the protein-binding capacity of such polyelectrolyte-modified membranes 3-6-fold. The low adsorption pH generates a high density of -COOH groups that function as either ion-exchange sites or points for covalent immobilization of metal-ion complexes that selectively bind tagged proteins. When functionalized with nitrilotriacetate (NTA)-Ni(2+) complexes, membranes containing PAA/polyethylenimine (PEI)/PAA films bind 93 mg of histidine(6)-tagged (His-tagged) ubiquitin per cm(3) of membrane. Additionally these membranes isolate His-tagged COP9 signalosome complex subunit 8 from cell extracts and show >90% recovery of His-tagged ubiquitin. Although modification with polyelectrolyte films occurs by simply passing polyelectrolyte solutions through the membrane for as little as 5 min, with low-pH deposition the protein binding capacities of such membranes are as high as for membranes modified with polymer brushes and 2-3-fold higher than for commercially available immobilized metal affinity chromatography (IMAC) resins. Moreover, the buffer permeabilities of polyelectrolyte-modified membranes that bind His-tagged protein are ~30% of the corresponding permeabilities of unmodified membranes, so protein capture can occur rapidly with low-pressure drops. Even at a solution linear velocity of 570 cm/h, membranes modified with PAA/PEI/PAA exhibit a lysozyme dynamic binding capacity (capacity at 10% breakthrough) of ~40 mg/cm(3). Preliminary studies suggest that these membranes are stable under depyrogenation conditions (1 M NaOH).

Translocation of stiff polymers through a nanopore driven by binding particles.

We investigate the translocation of stiff polymers in the presence of binding particles through a nanopore by two-dimensional Langevin dynamics simulations. We find that the mean translocation time shows a minimum as a function of the binding energy ε and the particle concentration φ, due to the interplay of the force from binding and the frictional force. Particularly, for the strong binding the translocation proceeds with a decreasing translocation velocity induced by a significant increase of the frictional force. In addition, both ε and φ have a notable impact on the distribution of the translocation time. With increasing ε and φ, it undergoes a transition from an asymmetric and broad distribution under the weak binding to a nearly Gaussian one under the strong binding, and its width becomes gradually narrower.

Computational Insights into the Esterification of Palmitic Acid with Methanol in Water.

This work provides quantified explanations for the thermodynamic and kinetic characteristics of esterification in aqueous phase, and how phase transfer catalysts improve water phase esterification of fatty acids in a computational-experimental way. Self-catalyzed reaction mode with or without solvation effects, water participated reaction mode, and catalytic reaction mode (catalyzed by p-dodecyl benzene sulfonic acid, DBSA) are discussed. Our results show that the initial self-catalytic reaction mode undergoes the energy barrier of 100.1 kJ/mol, and rises to 148.9 kJ/mol when water molecule is involved, which hinders the esterification reaction. With the DBSA catalyst, this energy barrier will drop to 97.5 kJ/mol and the water phase esterification is successfully promoted with the yield of 81%. The key kinetic factor of binding energy is discussed as that water molecule has a strong reactant binding competitiveness (with the binding energy of -57.9 kJ/mol, and the value for the non-aqueous phase mode is 3.0 kJ/mol) and DBSA has the binding energy with the value of -45.3 kJ/mol, so it can compete with water to form reactant complexes. This work is a successful practice of a computation-experiment combined scheme, and provides a quantitative basis for the improvement of phase transfer catalysts on water phase esterification reactions. The calculation mode and method of aqueous esterification make it possible to convert bio-based fatty acids into fatty acid esters in fermentation broth.

Structure-property relationship of nitramino oxetane polymers: a computational study on the effect of pendant chains.

A comprehensive study of the effect of the structure of pendant chains on the energetic and mechanical properties of nitramino oxetane polymers has been conducted. Enthalpy of formation (EOF), density, glass transition temperature, and elastic moduli were calculated via quantum mechanics and molecular dynamic simulations. It is shown in this study that -CH2 groups are unfavorable for EOFs, densities, and elastic moduli of the polymers, whereas -NCH3NO2 groups are favorable for these parameters. The glass transition temperature (T g) shows non-monotonic features with increasing -CH2 groups; it reaches a minimum value when the pendant chains consist of 1 or 2 -CH2 groups. Moreover, the location of the pendant chains can strongly affect T g of the polymers. Our study suggests that the asymmetric structure, distantly located pendant chains and appropriate length of the pendant chains can effectively reduce T g of the polymers with negligible compromise to other properties.

Structural evolution of LiN n + (n = 2, 4, 6, 8, and 10) clusters: mass spectrometry and theoretical calculations.

Mixed nitrogen-lithium cluster cations LiN n + were generated by laser vaporization and analyzed by time-of-flight mass spectrometry. It is found that LiN8 + has the highest ion abundance among the LiN n + ions in the mass spectrum. Density functional calculations were conducted to search for the stable structures of the Li-N clusters. The theoretical results show that the most stable isomers of LiN n + clusters are in the form of Li+(N2) n/2, and the order of their calculated binding energies is consistent with that of Li-N2 bond lengths. The most stable structures of LiN n + evolve from one-dimensional linear type (C ∞v, n = 2; D ∞h, n = 4), to two-dimensional branch type (D 3h, n = 6), then to three-dimensional tetrahedral (T d, n = 8) and square pyramid (C 4v, n = 10) types. Further natural bond orbital analyses show that electrons are transferred from the lone pair on Nα of every N2 unit to the empty orbitals of lithium atom in LiN2-8 +, while in LiN10 +, electrons are transferred from the bonding orbital of the Li-Nα bonds to the antibonding orbital of the other Li-Nα bonds. In both cases, the N2 units become dipoles and strongly interact with Li+. The average second-order perturbation stabilization energy for LiN8 + is the highest among the observed LiN n + clusters. For neutral LiN2-8 clusters, the most stable isomers were also formed by a Li atom and n/2 number of N2 units, while that of LiN10 is in the form of Li+(N2)3(η1-N4).

Roads to pentazolate anion: a theoretical insight.

The formation mechanism of pentazolate anion (PZA) is not yet clear. In order to present the possible formation pathways of PZA, the potential energy surfaces of phenylpentazole (PPZ), phenylpentazole radical (PPZ-R), phenylpentazole radical anion (PPZ-RA), PPZ and m-chloroperbenzoic acid (m-CPBA), p-pentazolylphenolate anion (p-PZPolA) and m-CPBA, and p-pentazolylphenol (p-PZPol) and m-CPBA were calculated by the computational electronic structure methods including the hybrid density functional, the double hybrid density functional and the coupled-cluster theories. At the thermodynamic point of view, the cleavages of C-N bonds of PPZ and PPZ-R need to absorb large amounts of heat. Thus, they are not feasible entrance for PZA formation at ambient condition. But excitation of PPZ and deprotonation of PPZ-RA probably happen before cleavage of C-N bond of PPZ at high-energy condition. As to the radical anion mechanism, the high accuracy calculations surveyed that the barrier of PZA formation is probably lower than that of dinitrogen evolution, but the small ionization potential of PPZ-RA gives rise to the unstable ionic pair of sodium PPZ at high temperature. In respect of oxidation mechanism, except for PPZ, the reactions of p-PZPolA and p-PZPol with m-CPBA can form PZA and quinone. The PZA formations have the barriers of about 20 kcal mol-1 which compete with the dinitrogen evolutions. The stabilities of PZA in both solid and gas phases were also studied herein. The proton prefers to transfer to pentazolyl group in the (N5)6(H3O)3(NH4)4Cl system which leads to the dissociation of pentazole ring. The ground states of M(N5)2(H2O)4 (M = Co, Fe and Mn) are high-spin states. The pentazolyl groups confined by the crystal waters in the coordinate compounds can improve the kinetic stability. As to the reactivity of PZA, it can be persistently oxidized by m-CPBA to oxo-PZA and 1,3-oxo-PZA with the barriers of about 20 kcal mol-1.

Adsorption behavior of acetone solvent at the HMX crystal faces: A molecular dynamics study.

Molecular dynamics simulations have been performed to understand the adsorption behavior of acetone (AC) solvent at the three surfaces of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctan (HMX) crystal, i.e. (011), (110), and (020) faces. The simulation results show that the structural features and electrostatic potentials of crystal faces are determined by the HMX molecular packing, inducing distinct mass density distribution, dipole orientation, and diffusion of solvent molecules in the interfacial regions. The solvent adsorption is mainly governed by the van der Waals forces, and the crystal-solvent interaction energies among three systems are ranked as (020)≈(110)>(011). The adsorption sites for solvent incorporation at the crystal surface were found and visualized with the aid of occupancy analysis. A uniform arrangement of adsorption sites is observed at the rough (020) surface as a result of ordered adsorption motif.

Face-Dependent Solvent Adsorption: A Comparative Study on the Interfaces of HMX Crystal with Three Solvents.

To understand the crystal-solvent interfacial interactions on the molecular scale, the interfaces between three solvents, that is, acetone, γ-butyrolactone, and cyclohexanone, and three growth faces of 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) crystal have been investigated with the aid of theoretical chemistry. The results show that the structural features of crystal faces play a critical role in the energetic, structural, and dynamic properties at the interfaces. For each solvent, the same change trend of some properties among the three faces of HMX crystal is observed, including adsorption affinity, local mass density, and solvent diffusion. For example, the rate of solvent diffusion at the three faces ranks as (011) > (110) > (020) regardless of solvent species. This can be attributed to the similar adsorption sites for solvent incorporation at the same face, which are concentrated at the cavities formed by surficial HMX molecules.

Study on the computer-aided design of high energetic compounds based on the 1,2,3,4-tetrazine-1,3-dioxide frame.

In order to discover more potential high energy compounds, five computer-aided design methods were founded, and 20 high energetic compounds based on the 1,2,3,4-tetrazine-1,3-dioxide frame were designed. The first step of computer-aided design methods was to design new frame M. Three combination rules were invented, they were simple double-points rule, complicated double-points rule, and complicated multi-points rule. The second step of computer-aided design methods was to design 1,2,3,4-tetrazine 1,3-dioxides derivants by connecting M to 1,2,3,4-tetrazine-1,3-dioxides. Two combination rules were invented, they were simple single-points rule and double-points rule. All the structures are ring-fused or caged compounds including 1,2,3,4-tetrazine-1,3-dioxide. In these compounds, almost half of them have positive or zero oxygen balances, and the nitrogen contents of 17 compounds are over 40%. The densities and detonation velocities of all compounds are over 1.98 g cm-3 and 9500 m s-1 respectively. -N = N- group and -NO2 group have a major contribution to enthalpy of formation, detonation heat, and power index. -O- group and -ONO2 group have the main contribution to density, detonation velocity, and detonation pressure.