Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Computational Insights.

Mechanism-based inactivation (MBI) refers to the metabolic bioactivation of a xenobiotic by cytochrome P450s to a highly reactive intermediate which subsequently binds to the enzyme and leads to the quasi-irreversible or irreversible inhibition. Xenobiotics, mainly drugs with specific functional units, are the major sources of MBI. Two possible consequences of MBI by medicinal compounds are drug-drug interaction and severe toxicity that are observed and highlighted by clinical experiments. Today almost all of these latent functional groups (e.g., thiophene, furan, alkylamines, etc.) are known, and their features and mechanisms of action, owing to the vast experimental and theoretical studies, are determined. In the past decade, molecular modeling techniques, mostly density functional theory, have revealed the most feasible mechanism that a drug undergoes by P450 enzymes to generate a highly reactive intermediate. In this review, we provide a comprehensive and detailed picture of computational advances toward the elucidation of the activation mechanisms of various known groups with MBI activity. To this aim, we briefly describe the computational concepts to carry out and analyze the mechanistic investigations, and then, we summarize the studies on compounds with known inhibition activity including thiophene, furan, alkylamines, terminal acetylene, etc. This study can be reference literature for both theoretical and experimental (bio)chemists in several different fields including rational drug design, the process of toxicity prevention, and the discovery of novel inhibitors and catalysts.

Distribution of atmospheric gaseous elemental mercury (Hg(0)) from the Sea of Japan to the Arctic, and Hg(0) evasion fluxes in the Eastern Arctic Seas: Results from a joint Russian-Chinese cruise in 2018.

The Eastern Arctic Seas and the north-western Pacific are among the most poorly investigated areas as far as Hg cycling in marine systems is concerned. Continuous measurements of gaseous elemental mercury (Hg(0)) concentrations in the marine boundary layer and Hg(0) evasion fluxes from the sea surface were performed in these regions in fall 2018. Atmospheric Hg(0) concentrations of 1.02-2.50 ng/m3 were measured (average: 1.45 ± 0.12 ng/m3; N = 2518). Values in the Far Eastern Seas of Russia were lower compared to previous observations, presumably reflecting а global trend of decreasing atmospheric Hg(0). Concentration-weighted trajectory analysis highlighted three source regions influencing Hg(0) concentrations in the ambient air during the cruise: 1) the north-eastern China and the Yellow Sea region; 2) the Kuril-Kamchatka region of the Pacific Ocean and the region around the Commander and Aleutian Islands; and 3) the Arctic region. In the Arctic, sea-air Hg(0) evasion fluxes were at the same low levels as those observed earlier in the northern sea areas (0.28-1.35 ng/m2/h, average, 0.70 ± 0.26 ng/m2/h, N = 29). In the Eastern Arctic Seas, Hg(0) evasion fluxes were significantly dependent on river runoff. In the Arctic Ocean, they were negatively correlated with water temperature and positively correlated with salinity, suggesting a proximity to areas with contiguous ice and higher dissolved Hg(0) concentrations in the surface seawater. These findings are consistent with the hypothesis that the Arctic Ocean is a source of atmospheric Hg(0) during late summer and fall.

Toward Ultracold Organic Chemistry: Prospects of Laser Cooling Large Organic Molecules.

Ultracold organic chemistry enables studies of reaction dynamics and mechanisms in the quantum regime. Access to ultracold molecules hinges on the ability to efficiently scatter multiple photons via quasi-closed cycling transitions. Optical cycling in polyatomic molecules is challenging due to their complex electronic structure. Using equation-of-motion coupled-cluster calculations, we demonstrate that an alkaline earth metal attached to various aromatic ligands (such as benzene, phenol, cyclopentadienyl, and pyrrolide) offers nearly closed cycling transitions with only a few additional repump lasers. We also show that aromatic ligands such as benzene can accommodate multiple cycling centers in various geometrical arrangements, opening new avenues in quantum information science, precision measurements, and ultracold chemistry.

In search of molecular ions for optical cycling: a difficult road.

Optical cycling, a continuous photon scattering off atoms or molecules, plays a central role in the quantum information science. While optical cycling has been experimentally achieved for many neutral species, few molecular ions have been investigated. We present a systematic theoretical search for diatomic molecular ions suitable for optical cycling using equation-of-motion coupled-cluster methods. Inspired by the electronic structure patterns of laser-cooled neutral molecules, we establish the design principles for molecular ions and explore various possible cationic molecular frameworks. The results show that finding a perfect molecular ion for optical cycling is challenging, yet possible. Among various possible diatomic molecules we suggest several candidates, which require further attention from both theory and experiment: YF+, SiO+, PN+, SiBr+, and BO+.

Long-Range N-N Bonding by Rydberg Electrons.

By using high-level ab initio methods, we examine the nature of bonding between Rydberg electrons hosted by two four-coordinate nitrogen centers embedded in a hydrocarbon scaffold. The electronic structure of these species resembles that of diradicals, yet the diffuse nature of the orbitals hosting the unpaired electrons results in unusual features. The unpaired Rydberg electrons exhibit long-range bonding interactions, leading to stabilization of the singlet state (relative to the triplet) and a reduced number of effectively unpaired electrons. However, thermochemical gains due to through-space bonding are offset by strong Coulomb repulsion between positively charged nitrogen cores. The kinetic stability of these Rydberg diradicals may be controlled by a judicious choice of the molecular scaffold, suggesting possible strategies for their experimental characterization.

Two Cycling Centers in One Molecule: Communication by Through-Bond Interactions and Entanglement of the Unpaired Electrons.

Many applications in quantum information science (QIS) rely on the ability to laser-cool molecules. The scope of applications can be expanded if laser-coolable molecules possess two or more cycling centers, i.e., moieties capable of scattering photons via multiple absorption-emission events. Here we employ the equation-of-motion coupled-cluster method for double electron attachment (EOM-DEA-CCSD) to study the electronic structure of hypermetallic molecules with two alkaline-earth metals connected by an acetylene linker. The electronic structure of the molecules is similar to that of two separated alkali metals; however, the interaction between the two electrons is weak and largely dominated by through-bond interactions. The communication between the two cycling centers is quantified by the extent of the entanglement of the two unpaired electrons associated with the two cycling centers. This contribution highlights the rich electronic structure of hypermetallic molecules that may advance various applications in QIS and beyond.

Towards a rational design of laser-coolable molecules: insights from equation-of-motion coupled-cluster calculations.

Access to cold molecules is critical for quantum information science, design of new sensors, ultracold chemistry, and search of new phenomena. These applications depend on the ability to laser-cool molecules. Rigorous theory and qualitative models can play a central role in narrowing down the vast pool of potential candidates amenable to laser cooling. We report a systematic study of structural and optical properties of alkaline earth metal derivatives in the context of their applicability in laser cooling using equation-of-motion coupled-cluster methods. To rationalize and generalize the results from high-level electronic structure calculations, we develop an effective Hamiltonian model. The model explains the observed trends and suggests new principles for the design of laser-coolable molecules.

Improving Performance of the SMD Solvation Model: Bondi Radii Improve Predicted Aqueous Solvation Free Energies of Ions and pKa Values of Thiols.

Calculation of the solvation free energy of ionic molecules is the principal source of errors in the quantum chemical evaluation of pKa values using implicit polarizable continuum solvent models. One of the important parameters affecting the performance of these models is the choice of atomic radii. Here, we assess the performance of the solvation model based on density (SMD) implicit solvation model employing SMD default radii (SMD) and Bondi radii (SMD-B), a set of empirical atomic radii developed based on the crystallographic data. For a set of 112 ions (60 anions and 52 cations), the SMD-B model showed lower mean unsigned error (MUE) for predicted aqueous solvation free energies (4.0 kcal/mol for anions and 2.4 kcal/mol for cations) compared to the standard SMD model (MUE of 5.0 kcal/mol for anions and 2.9 kcal/mol for cations). In particular, usage of Bondi radii improves the aqueous solvation energies of sulfur-containing ions by >5 kcal/mol compared to the SMD default radii. Indeed, for a set of 45 thiols, the SMD-B model was found to dramatically improve the predicted pKa values, with ∼1 pKa unit mean deviation from the experimental values, compared to ∼7 pKa units mean deviation for the SMD model with the default radii. These findings highlight the importance of the choice of atomic radii on the performance of the implicit solvation models.

Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance.

The import of superoxide dismutase-2 (SOD2) into mitochondria is vital for the survival of eukaryotic cells. SOD2 is encoded within the nuclear genome and translocated into mitochondria for activation after translation in the cytosol. The molecular chaperone Hsp70 modulates SOD2 activity by promoting import of SOD2 into mitochondria. In turn, the activity of Hsp70 is controlled by co-chaperones, particularly CHIP, which directs Hsp70-bound proteins for degradation in the proteasomes. We investigated the mechanisms controlling the activity of SOD2 to signal activation and maintain mitochondrial redox balance. We demonstrate that Akt1 binds to and phosphorylates the C terminus of Hsp70 on Serine631, which inhibits CHIP-mediated SOD2 degradation thereby stabilizing and promoting SOD2 import. Conversely, increased mitochondrial-H2O2 formation disrupts Akt1-mediated phosphorylation of Hsp70, and non-phosphorylatable Hsp70 mutants decrease SOD2 import, resulting in mitochondrial oxidative stress. Our findings identify Hsp70 phosphorylation as a physiological mechanism essential for regulation of mitochondrial redox balance.

Vertical vs. adiabatic ionization energies in solution and gas-phase: probing ionization-induced reorganization in conformationally-mobile bichromophoric actuators using photoelectron spectroscopy, electrochemistry and theory.

Ionization-induced structural and conformational reorganization in various π-stacked dimers and covalently linked bichromophores is relevant to many processes in biological systems and functional materials. In this work, we examine the role of structural, conformational, and solvent reorganization in a set of conformationally mobile bichromophoric donors, using a combination of gas-phase photoelectron spectroscopy, solution-phase electrochemistry, and density functional theory (DFT) calculations. Photoelectron spectral analysis yields both adiabatic and vertical ionization energies (AIE/VIE), which are compared with measured (adiabatic) solution-phase oxidation potentials (Eox). Importantly, we find a strong correlation of Eox with AIE, but not VIE, reflecting variations in the attendant structural/conformational reorganization upon ionization. A careful comparison of the experimental data with the DFT calculations allowed us to probe the extent of charge stabilization in the gas phase and solution and to parse the reorganizational energy into its various components. This study highlights the importance of a synergistic approach of experiment and theory to study ionization-induced structural and conformational reorganization.

An Electron-Rich Calix[4]arene-Based Receptor with Unprecedented Binding Affinity for Nitric Oxide.

Calixarenes have found widespread application as building blocks for the design and synthesis of functional materials in host-guest chemistry. The ongoing desire to develop a detailed understanding of the nature of NO bonding to multichromophoric π-stacked assemblies led us to develop an electron-rich methoxy derivative of calix[4]arene (3), which we show exists as a single conformer in solution at ambient temperature. Here, we examine the redox properties of this derivative, generate its cation radical (3+. ) using robust chemical oxidants, and determine the relative efficacy of its NO binding in comparison with model calixarenes. We find that 3/3+. is a remarkable receptor for NO+ /NO, with unprecedented binding efficacy. The availability of precise experimental structures of this calixarene derivative and its NO complex, obtained by X-ray crystallography, is critically important both for developing novel functional NO biosensors, and understanding the role of stacked aromatic donors in efficient NO binding, which may have relevance to biological NO transport.

Molecular Actuators in Action: Electron-Transfer-Induced Conformation Transformation in Cofacially Arrayed Polyfluorenes.

There is much current interest in the design of molecular actuators, which undergo reversible, controlled motion in response to an external stimulus (light, heat, oxidation, etc.). Here we describe the design and synthesis of a series of cofacially arrayed polyfluorenes (MeF nH m) with varied end-capping groups, which undergo redox-controlled electromechanical actuation. Such cofacially arrayed polyfluorenes are a model molecular scaffold to investigate fundamental processes of charge and energy transfer across a π-stacked assembly, and we show with the aid of NMR and optical spectroscopies, X-ray crystallography and DFT calculations that in the neutral state the conformation of MeF nH1 and MeF nH2 is open rather than cofacial, with a conformational dependence that is highly influenced by the local environment. Upon (electro)chemical oxidation, these systems undergo a reversible transformation into a closed fully π-stacked conformation, driven by charge-resonance stabilization of the cationic charge. These findings are expected to aid the design of novel wire-like cofacially arrayed systems capable of undergo redox-controlled actuation.

An electron-transfer induced conformational transformation: from non-cofacial "sofa" to cofacial "boat" in cyclotetraveratrylene (CTTV) and formation of charge transfer complexes.

Electro-active polychromophoric assemblies that undergo clam-like electromechanic actuation represent an important class of organic functional materials. Here, we show that the readily available cyclotetraveratrylene (CTTV) undergoes oxidation-induced folding, consistent with interconversion from a non-cofacial "sofa" conformation to a cofacial "boat" conformer. It is found that the non-cofacial "sofa" conformer of CTTV forms stable electron donor-acceptor complexes with chloranil and DDQ. Electron-transfer induced conformational transformation in CTTV provides a framework for the rational design of novel organic functional molecules.

Game of Frontier Orbitals: A View on the Rational Design of Novel Charge-Transfer Materials.

Since the first application of frontier molecular orbitals (FMOs) to rationalize stereospecificity of pericyclic reactions, FMOs have remained at the forefront of chemical theory. Yet, the practical application of FMOs in the rational design and synthesis of novel charge transfer materials remains under-appreciated. In this Perspective, we demonstrate that molecular orbital theory is a powerful and universal tool capable of rationalizing the observed redox/optoelectronic properties of various aromatic hydrocarbons in the context of their application as charge-transfer materials. Importantly, the inspection of FMOs can provide instantaneous insight into the interchromophoric electronic coupling and polaron delocalization in polychromophoric assemblies, and therefore is invaluable for the rational design and synthesis of novel materials with tailored properties.

Towards the rational design of novel charge-transfer materials: biaryls with a dihedral angle-independent hole delocalization mechanism.

Biaryl cation radicals are important electroactive materials, which show two mechanisms of hole delocalization: static delocalization at small interplanar dihedral angles and dynamic hopping at larger angles, reflecting the interplay between electronic coupling and structural reorganization. Herein, we describe the rational design of biaryls possessing an invariant hole delocalization mechanism.

The Role of Torsional Dynamics on Hole and Exciton Stabilization in π-Stacked Assemblies: Design of Rigid Torsionomers of a Cofacial Bifluorene.

Exciton and charge delocalization across π-stacked assemblies is of importance in biological systems and functional polymeric materials. To examine the requirements for exciton and hole stabilization, cofacial bifluorene (F2) torsionomers were designed, synthesized, and characterized: unhindered (model) Me F2, sterically hindered tBu F2, and cyclophane-like C F2, where fluorenes are locked in a perfect sandwich orientation via two methylene linkers. This set of bichromophores with varied torsional rigidity and orbital overlap shows that exciton stabilization requires a perfect sandwich-like arrangement, as seen by strong excimeric-like emission only in C F2 and Me F2. In contrast, hole delocalization is less geometrically restrictive and occurs even in sterically hindered tBu F2, as judged by 160 mV hole stabilization and a near-IR band in the spectrum of its cation radical. These findings underscore the diverse requirements for charge and energy delocalization across π-stacked assemblies.

Strength of π-Stacking, from Neutral to Cation: Precision Measurement of Binding Energies in an Isolated π-Stacked Dimer.

π-Stacking interactions are ubiquitious across chemistry and biochemistry, impacting areas from organic materials and photovoltaics to biochemistry and DNA. However, experimental data is lacking regarding the strength of π-stacking forces-an issue not settled even for the simplest model system, the isolated benzene dimer. Here, we use two-color appearance potential measurements to determine the binding energies of the isolated, π-stacked dimer of fluorene (C13H10) in ground, excited, and ionic states. Our measurements provide the first precise values for π-stacking interaction energies in these states, which are key benchmarks for theory. Indeed, theoretical predictions using ab initio and carefully benchmarked DFT methods are in excellent agreement with experiment.

From Static to Dynamic: Electron Density of HOMO at Biaryl Linkage Controls the Mechanism of Hole Delocalization.

In order to extend the physical length of hole delocalization in a molecular wire, chromophores of increasing size are often desired. However, the effect of size on the efficacy and mechanism of hole delocalization remains elusive. Here, we employ a model set of biaryls to show that with increasing chromophore size, the mechanism of steady-state hole distribution switches from static delocalization in biaryls with smaller chromophores to dynamic hopping, as exemplified in the largest system, tBuHBC2 (i.e., "superbiphenyl"), which displays a vanishingly small electronic coupling. This important finding is analyzed with the aid of Hückel molecular orbital and Marcus-Hush theories. Our findings will enable the rational design of the novel molecular wires with length-invariant redox/optical properties suitable for long-range charge transfer.

From Intramolecular (Circular) in an Isolated Molecule to Intermolecular Hole Delocalization in a Two-Dimensional Solid-State Assembly: The Case of Pillarene.

To achieve long-range charge transport/separation and, in turn, bolster the efficiency of modern photovoltaic devices, new molecular scaffolds are needed that can self-assemble in two-dimensional (2D) arrays while maintaining both intra- and intermolecular electronic coupling. In an isolated molecule of pillarene, a single hole delocalizes intramolecularly via hopping amongst the circularly arrayed hydroquinone ether rings. The crystallization of pillarene cation radical produces a 2D self-assembly with three intermolecular dimeric (sandwich-like) contacts. Surprisingly, each pillarene in the crystal lattice bears a fractional formal charge of +1.5. This unusual stoichiometry of oxidized pillarene in crystals arises from effective charge distribution within the 2D array via an interplay of intra- and intermolecular electronic couplings. This important finding is expected to help advance the rational design of efficient solid-state materials for long-range charge transfer.