Enhanced stereodivergent evolution of carboxylesterase for efficient kinetic resolution of near-symmetric esters through machine learning.

Carboxylesterases serve as potent biocatalysts in the enantioselective synthesis of chiral carboxylic acids and esters. However, naturally occurring carboxylesterases exhibit limited enantioselectivity, particularly toward ethyl 3-cyclohexene-1-carboxylate (CHCE, S1), due to its nearly symmetric structure. While machine learning effectively expedites directed evolution, the lack of models for predicting the enantioselectivity for carboxylesterases has hindered progress, primarily due to challenges in obtaining high-quality training datasets.

Semirational Design Strategy To Enhance the Thermostability and Catalytic Activity of Cytochrome P450 105D7 for the Degradation of the Pharmaceutically Active Compounds: Diclofenac.

Pharmaceutically active compounds are an important category of emerging pollutants, and their biological transformation processes in the environment are crucial for understanding and evaluating the migration, transformation, and environmental fate of emerging pollutants. The cytochrome P450 105 enzyme family has been proven to play an important role in the degradation of exogenous environmental pollutants. However, its thermostability and catalytic activity still need to be improved to better adapt to complex environmental conditions.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents.

Biocatalytic strategy for the construction of sp-rich polycyclic compounds from directed evolution and computational modelling.

Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Given their widespread presence in bioactive molecules, methods for the asymmetric synthesis of these molecules, in particular through the selective functionalization of ubiquitous yet unreactive aliphatic C-H bonds, are highly desirable. In this study, we report the development of a novel strategy for the asymmetric synthesis of 4-, 5-, and 6-membered lactams via an unprecedented hemoprotein-catalyzed intramolecular C-H amidation reaction with readily available dioxazolone reagents.

Computational Exploration of Anomalous Regioselectivities in Cycloadditions of Ketenes to Oxazolines.

Thermal (2 + 2) cycloadditions of several -carboalkoxy ()-2--butyldihydrooxazoles with ketenes have been studied experimentally by the Ghosez group. Contrary to results from Seebach and co-workers that the electrophilic addition of acylating agents occurs β to dihydrooxazole nitrogen, Ghosez found major cycloadducts resulting from an attack of ketene carbonyl carbon β to oxygen. We investigate the potential energy surface for the cycloaddition of diphenyl- and phenylchloroketenes to two ()-2--butyldihydrooxazoles with ωB97X-D and mPW1PW91 density functional theory and DLPNO-CCSD(T) wave function theory.

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging.

Metabolic activation mechanism of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) by cytochrome P450 2B6: A QM/MM approach.

Cytochrome P450 enzymes (CYPs) play an essential role in the bio-transformation of polychlorinated biphenyls (PCBs). The present work implemented quantum mechanic/molecular mechanic methods (QM/MM) and density functional theory (DFT) to study the metabolic activation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) catalyzed by CYP2B6. Electrophilic additions at the C and C positions generate different active intermediates.

Computational study on the metabolic activation mechanism of PeCDD by Cytochrome P450 1A1.

Cytochrome P450 enzymes (CYPs) are crucial for metabolizing dioxin compounds such as 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD). Here we have applied molecular dynamic simulations (MD), quantum mechanics/molecular mechanics methods (QM/MM) and density functional theory (DFT) to investigate the metabolic activation and transformation of PeCDD catalyzed by CYP1A1. Our QM/MM calculations highlight that PeCDD can be activated by P450s through the well-known electrophilic addition mechanism with an average energy barrier of 20.

Degradation mechanism of biphenyl and 4-4'-dichlorobiphenyl cis-dihydroxylation by non-heme 2,3 dioxygenases BphA: A QM/MM approach.

Biphenyl 2,3-dioxygenase (BphA), a Rieske-type and first enzyme in the aerobic degradation process, plays a key role in the metabolizing process of biphenyl/polychlorinated biphenyl aromatic pollutants in the environment. To understand the catalytic mechanism of biphenyl 2,3-dioxygenase, the conversions leading to the cis-diols are investigated by means of quantum mechanics/molecular mechanics (QM/MM) method. A hydroperoxo-iron (III) species is involved in the enzyme-catalyzed reaction.

Experimental Investigation on the Nonlinear Coupled Flutter Motion of a Typical Flat Closed-Box Bridge Deck.

The nonlinear post-flutter instabilities were experimentally investigated through two-degree-of-freedom sectional model tests on a typical flat closed-box bridge deck (width-to-depth ratio 9.14). Laser displacement sensors and piezoelectric force balances were used in the synchronous measurement of dynamic displacement and aerodynamic force.

Degradation mechanism for Zearalenone ring-cleavage by Zearalenone hydrolase RmZHD: A QM/MM study.

The danger of zearalenone (ZEN) as an endocrine disruptor to humans and the environment has aroused increasing attention. In this study, we implemented the quantum mechanics/molecular mechanics (QM/MM) method to investigate the degradation mechanism of ZEN hydrolase (RmZHD) toward ZEN at the atomic level. The degradation process involves two concerted reaction pathways, where the active site contains a Ser-His-Glu triplet as a proton donor.

Biodegradation mechanism of polyesters by hydrolase from Rhodopseudomonas palustris: An in silico approach.

Massively used plastics have caused worldwide environmental concerns. Polyesters like polylactic acid (PLA) are one of the mostly used plastics due to its excellent physical and chemical properties and low-cost advantages. It is critical to develop the elimination and recycle techniques for polyesters.

Catalytic Mechanism for 2,3-Dihydroxybiphenyl Ring Cleavage by Nonheme Extradiol Dioxygenases BphC: Insights from QM/MM Analysis.

An extradiol-cleaving catecholic dioxygenase, 2,3-dihydroxybiphenyl dioxygenase, plays important roles in the catabolism of biphenyl/polychlorinated biphenyl aromatic contaminants in the environment. To better elucidate the biodegradable pathway, a theoretical investigation of the ring-opening degradation of 2,3-dihydroxybiphenyl (DHBP) was performed with the aid of quantum mechanical/molecular mechanical calculations. A quintet state of the DHBP-iron-dioxygen group adducts was found to be the reactive state with a substrate radical-Fe-superoxo (DHBP-Fe-O) character.

Computational evidence for the degradation mechanism of haloalkane dehalogenase LinB and mutants of Leu248 to 1-chlorobutane.

The catalytic degradation ability of the haloalkane dehalogenase LinB toward 1-chlorobutane (1-CB) was studied using a combined quantum mechanics/molecular mechanics (QM/MM) approach. Two major processes are involved in the LinB-catalyzed removal of halogens: dechlorination and hydrolyzation. The present study confirmed the experimentally proposed reaction path at the molecular level.

QM/MM study of the reaction mechanism of Cl-cis,cis-muconate with muconate lactonizing enzyme.

The lactonization process of Cl-cis,cis-muconate catalyzed by anti-muconate lactonizing enzyme (anti-MLE) was studied theoretically with the aid of a combined quantum mechanics/molecular mechanics (QM/MM) approach. Two elementary processes steps involved in the lactanization process were investigated. The calculated energy barriers agree well with the experimental values.

The growth mechanism of polycyclic aromatic hydrocarbons from the reactions of anthracene and phenanthrene with cyclopentadienyl and indenyl.

Polycyclic aromatic hydrocarbons (PAHs) are highly toxic, mutagenic and/or carcinogenic to humans. To reduce the emission of PAHs, it's significant and indispensable to explore the PAH formation mechanism. In the present work, the growth mechanism of PAHs from the reactions of anthracene and phenanthrene with cyclopentadienyl and indenyl radicals was investigated with the aid of high-accuracy quantum chemistry calculation.

Adsorption of bisphenol A to a carbon nanotube reduced its endocrine disrupting effect in mice male offspring.

Soluble carbon nanotubes (CNTs) have shown promise as materials for adsorption of environmental contaminants such as Bisphenol A (BPA), due to the high adsorption capacity and strong desorption hysteresis of BPA on CNTs. The adsorption of BPA to CNTs may change the properties of both BPA and CNTs, and induce different toxicity to human and living systems from that of BPA and CNTs alone. Herein, we report that oral exposure of BPA/MWCNT-COOH (carboxylated multi-walled carbon nantubes) adduct to mice during gestation and lactation period decreased the male offspring reproductive toxicity compared with those induced by BPA alone.

Atmospheric oxidation mechanism and kinetic studies for OH and NO3 radical-initiated reaction of methyl methacrylate.

The mechanism for OH and NO3 radical-initiated oxidation reactions of methyl methacrylate (MMA) was investigated by using density functional theory (DFT) molecular orbital theory. Geometrical parameters of the reactants, intermediates, transition states, and products were fully optimized at the B3LYP/6-31G(d,p) level. Detailed oxidation pathways were presented and discussed.