Theoretical Study of the Oxidation of Methane to Methanol by the [CuIICuII(µ-O)2CuIII(7- N-Etppz)]1+ Complex.

The reactivity patterns of a series of trivalent copper complexes have been studied to gain a better understanding of the chemical reactions occurring at the active site of particulate methane monooxygenase (pMMO). In this study, hybrid density functional theory is used to study the oxidation of methane to methanol mediated by the [CuIICuII(µ-O)2CuIII(7- N-Etppz)]1+ complex. Reaction mechanisms in different spin states were explored. Based on the calculated free-energy profile, a mechanism is suggested for the reaction of the oxidation of methane to methanol. The first step (1 → 2) is a hydrogen transfer to the bridged oxygen in the Cu2O2 core from the methane to form a methyl radical. The second step (2 → 3) is the radical recombination, in which the bridged hydroxyl rotates upward and exposes the oxygen moiety toward the methyl radical to form methanol. The radical recombination step is rate-limiting, with a calculated free-energy barrier of 19.6 kcal mol-1, which is in good agreement with the experimental value of 18.4 kcal mol-1. The mixed valent bis(µ-oxo)CuIICuIII species in the Cu3O4 core is directly responsible for the C-H activation of methane.

Spin crossover dynamics studies on the thermally activated molecular oxygen binding mechanism on a model copper complex.

The theoretical description of the primary dioxygen (O2) binding and activation step in many copper or iron enzymes, suffers from the intrinsically electronic non-adiabaticity of the spin flip events of the triplet dioxygen molecule (3O2), mediated by spin-orbit couplings. In this work, we presented the early-stage ultrafast spin flip dynamics of O2 binding for a simplified monocopper complex, involving the coupled singlet and triplet electronic states. The on-the-fly trajectory surface hopping (TSH) simulations have identified the dynamical effects that may influence the mode of O2 coordination (end-on vs. side-on), and the electronic structures can be viewed as complexes of molecular O2 with Cu(i) or as Cu(ii)-superoxide compounds. In addition, significant spin flip events are obversed within the sub-picosecond regime. We hope this work may provide complimentary insights on the traditional interpretation of O2 binding on copper complexes and subsequent catalytic reaction mechanisms.

Hydrogen bond dynamics governs the effective photoprotection mechanism of plant phenolic sunscreens.

Sinapic acid derivatives are important sunscreen species in natural plants, which could provide protection from solar UV radiation. Using a combination of ultrafast excited state dynamics, together with classical molecular dynamics studies, we demonstrate that there is direct coupling of hydrogen bond motion with excited state photoprotection dynamics as part of the basic mechanism in solution. Beyond the intra-molecular degree of freedom, the inter-molecular motions on all timescales are potentially important for the photochemical or photophysical events, ranging from the ultrafast hydrogen bond motion to solvent rearrangements. This provides not only an enhanced understanding of the anomalous experimental spectroscopic results, but also the key idea in the development of sunscreen agents with improved photo-chemical properties. We suggest that the hydrogen bond dynamics coupled excited state photoprotection mechanism may also be possible in a broad range of bio-related molecules in the condensed phase.

Ultrafast structural flattening motion in photoinduced excited state dynamics of a bis(diimine) copper(I) complex.

The ultrafast photoinduced structural change dynamics of a prototypical Cu(I) complex, namely, [Cu(dmp)2](+) (dmp = 2,9-dimethyl-1,10-phenanthroline), is investigated based on the theoretical analysis of static and dynamical calculations at the all-atomic level. This work mainly focuses on the intriguing structural flattening features of [Cu(dmp)2](+) occurring in the metal-to-ligand charge transfer singlet excited state ((1)MLCT) on the sub-picosecond timescale. Our estimated time constant (∼ 675 fs) of this "flattening" motion is in good agreement with recent experimental values. The full-dimensional excited-state nonadiabatic dynamic simulation provides a direct view of the ultrafast photoinduced events of [Cu(dmp)2](+), especially, the structural flattening mechanism on the S1 state. Several molecular motions (such as Cu-N stretching, the motion of the substituted groups etc.) with distinguishable time scales are involved in the flattening dynamics. The Fourier transformation of the time-dependent oscillation of the Cu-N bond and the N-Cu-N bond angle provides consistent conclusions with the experimental spectrum analysis. These dynamics details imply that various nuclear motions are strongly coupled in the high-dimensional excited-state potential energy surface responsible for the geometrical evolution of [Cu(dmp)2](+). This work provides us a unique fundamental understanding of the ultrafast photoinduced excited-state nonadiabatic process of Cu(I) complexes and their derivatives, which should have potential impacts on various research fields, such as photo-catalysts, dye-sensitized solar cells (DSSCs), and organic light emitting diodes (OLEDs).

How Many Conformations of Enzymes Should Be Sampled for DFT/MM Calculations? A Case Study of Fluoroacetate Dehalogenase.

The quantum mechanics/molecular mechanics (QM/MM) method (e.g., density functional theory (DFT)/MM) is important in elucidating enzymatic mechanisms. It is indispensable to study "multiple" conformations of enzymes to get unbiased energetic and structural results. One challenging problem, however, is to determine the minimum number of conformations for DFT/MM calculations. Here, we propose two convergence criteria, namely the Boltzmann-weighted average barrier and the disproportionate effect, to tentatively address this issue. The criteria were tested by defluorination reaction catalyzed by fluoroacetate dehalogenase. The results suggest that at least 20 conformations of enzymatic residues are required for convergence using DFT/MM calculations. We also tested the correlation of energy barriers between small QM regions and big QM regions. A roughly positive correlation was found. This kind of correlation has not been reported in the literature. The correlation inspires us to propose a protocol for more efficient sampling. This saves 50% of the computational cost in our current case.

Theoretical analysis of excited states and energy transfer mechanism in conjugated dendrimers.

The excited states of the phenylene ethynylene dendrimer are investigated comprehensively by various electronic-structure methods. Several computational methods, including SCS-ADC(2), TDHF, TDDFT with different functionals (B3LYP, BH&HLYP, CAM-B3LYP), and DFT/MRCI, are applied in systematic calculations. The theoretical approach based on the one-electron transition density matrix is used to understand the electronic characters of excited states, particularly the contributions of local excitations and charge-transfer excitations within all interacting conjugated branches. Furthermore, the potential energy curves of low-lying electronic states as the functions of ethynylene bonds are constructed at different theoretical levels. This work provides us theoretical insights on the intramolecular excited-state energy transfer mechanism of the dendrimers at the state-of-the-art electronic-structure theories.

Application of polarizable ellipsoidal force field model to pnicogen bonds.

Noncovalent interactions, such as hydrogen bonds and halogen bonds, are frequently used in drug designing and crystal engineering. Recently, a novel noncovalent pnicogen bonds have been identified as an important driving force in crystal structures with similar bonding mechanisms as hydrogen bond and halogen bond. Although the pnicogen bond is highly anisotropic, the pnicogen bond angles range from 160° to 180° due to the complicated substituent effects. To understand the anisotropic characters of pnicogen bond, a modification of the polarizable ellipsoidal force field (PEff) model previously used to define halogen bonds was proposed in this work. The potential energy surfaces (PESs) of mono- and polysubstituted PH3 -NH3 complexes were calculated at CCSD(T), MP2, and density functional theory levels and were used to examine the modified PEff model. The results indicate that the modified PEff model can precisely characterize pnicogen bond. The root mean squared error of PES obtained with PEff model is less than 0.5 kcal/mol, compared with MP2 results. In addition, the modified PEff model may be applied to other noncovalent bond interactions, which is important to understand the role of intermolecular interactions in the self-assembly structures.

Photoinduced Ultrafast Intramolecular Excited-State Energy Transfer in the Silylene-Bridged Biphenyl and Stilbene (SBS) System: A Nonadiabatic Dynamics Point of View.

The photoinduced intramolecular excited-state energy-transfer (EET) process in conjugated polymers has received a great deal of research interest because of its important role in the light harvesting and energy transport of organic photovoltaic materials in photoelectric devices. In this work, the silylene-bridged biphenyl and stilbene (SBS) system was chosen as a simplified model system to obtain physical insight into the photoinduced intramolecular energy transfer between the different building units of the SBS copolymer. In the SBS system, the vinylbiphenyl and vinylstilbene moieties serve as the donor (D) unit and the acceptor (A) unit, respectively. The ultrafast excited-state dynamics of the SBS system was investigated from the point of view of nonadiabatic dynamics with the surface-hopping method at the TDDFT level. The first two excited states (S1 and S2) are characterized by local excitations at the acceptor (vinylstilbene) and donor (vinylbiphenyl) units, respectively. Ultrafast S2-S1 decay is responsible for the intramolecular D-A excitonic energy transfer. The geometric distortion of the D moiety play an essential role in this EET process, whereas the A moiety remains unchanged during the nonadiabatic dynamics simulation. The present work provides a direct dynamical approach to understand the ultrafast intramolecular energy-transfer dynamics in SBS copolymers and other similar organic photovoltaic copolymers.

A polarizable ellipsoidal force field for halogen bonds.

The anisotropic effects and short-range quantum effects are essential characters in the formation of halogen bonds. Since there are an array of applications of halogen bonds and much difficulty in modeling them in classical force fields, the current research reports solely the polarizable ellipsoidal force field (PEff) for halogen bonds. The anisotropic charge distribution was represented with the combination of a negative charged sphere and a positively charged ellipsoid. The polarization energy was incorporated by the induced dipole model. The resulting force field is "physically motivated," which includes separate, explicit terms to account for the electrostatic, repulsion/dispersion, and polarization interaction. Furthermore, it is largely compatible with existing, standard simulation packages. The fitted parameters are transferable and compatible with the general AMBER force field. This PEff model could correctly reproduces the potential energy surface of halogen bonds at MP2 level. Finally, the prediction of the halogen bond properties of human Cathepsin L (hcatL) has been found to be in excellent qualitative agreement with the cocrystal structures.

The reaction mechanism of hydroxyethylphosphonate dioxygenase: a QM/MM study.

By employing ab initio quantum mechanical/molecular mechanical (QM/MM) and molecular dynamics (MD) simulations, we have provided further evidence against the previously proposed hydroperoxylation or hydroxylation mechanism of hydroxyethylphosphonate dioxygenase (HEPD). HEPD employs an interesting catalytic cycle based on concatenated bifurcations. The first bifurcation is based on the abstraction of hydrogen atoms from the substrate, which leads to a distal or proximal hydroperoxo species (Fe-OOH or Fe-(OH)O). The second and the third bifurcations refer to the carbon-carbon bond cleavage reaction. And this is achieved through a tridentate intermediate, or employing a proton-shuttle assisted mechanism, in which the residue Glu(176) or the Fe(IV)=O group serves as a general base. The reaction directions seem to be tunable and show significant environment dependence. This mechanism can provide a comprehensive interpretation for the seemingly contradicting experimental evidences and provide insight into the development of biochemistry and material sciences.

How a single 5-methylation of cytosine regulates the recognition of C/EBPß transcription factor: a molecular dynamic simulation study.

CpG methylation can regulate gene expression by altering the specific binding of protein and DNA. In order to understand how a single 5mC regulates protein-DNA interactions, we have compared the structures and dynamics of CEBP/ßprotein-DNA complexes before and after methylation, and the results indicate that even a single 5mC can regulate protein-DNA recognition by steric-hindrance effect of methyl group and changing the hydrogen bond interactions. The interactions between the methyl group, mCpG motif, and the conserved residue arginine make the protein read out the variation of local environment, which further enhances the specific recognition and affects the base pair stacking. The stacking interactions can propagate along the backbone of DNA and lead to long-range allosteric effects, including obvious conformational variations for DNA base pairs.

Charge-Transfer Knowledge Graph among Amino Acids Derived from High-Throughput Electronic Structure Calculations for Protein Database.

The charge-transfer coupling is an important component in tight-binding methods. Because of the highly complex chemical structure of biomolecules, the anisotropic feature of charge-transfer couplings in realistic proteins cannot be ignored. In this work, we have performed the first large-scale quantitative assessment of charge-transfer preference by calculating the charge-transfer couplings in all 20 × 20 possible amino acid side-chain combinations, which are extracted from available high-quality structures of thousands of protein complexes. The charge-transfer database quantitatively shows distinct features of charge-transfer couplings among millions of amino acid side-chain combinations. The overall distribution of charge-transfer couplings reveals that only one average or representative structure cannot be regarded as the typical charge-transfer preference in realistic proteins. This work provides us an alternative route to comprehensively understand the charge-transfer couplings for the overall distribution of realistic proteins in the foreseen big data scenario.

Direct Learning Hidden Excited State Interaction Patterns from ab initio Dynamics and Its Implication as Alternative Molecular Mechanism Models.

The excited states of polyatomic systems are rather complex, and often exhibit meta-stable dynamical behaviors. Static analysis of reaction pathway often fails to sufficiently characterize excited state motions due to their highly non-equilibrium nature. Here, we proposed a time series guided clustering algorithm to generate most relevant meta-stable patterns directly from ab initio dynamic trajectories. Based on the knowledge of these meta-stable patterns, we suggested an interpolation scheme with only a concrete and finite set of known patterns to accurately predict the ground and excited state properties of the entire dynamics trajectories, namely, the prediction with ensemble models (PEM). As illustrated with the example of sinapic acids, The PEM method does not require any training data beyond the clustering algorithm, and the estimation error for both ground and excited state is very close, which indicates one could predict the ground and excited state molecular properties with similar accuracy. These results may provide us some insights to construct molecular mechanism models with compatible energy terms as traditional force fields.

Atomic Resolution Insights into the Structural Aggregations and Optical Properties of Neat Imidazolium-Based Ionic Liquids.

A fundamental understanding of the structural heterogeneity and optical properties of ionic liquids is crucial for their potential applications in catalysis, optical measurement, and solar cells. Herein, a synergistic approach combining molecular dynamics simulations, excited-state calculations, and statistical analysis was used to explore the explicit correlation between the structural and optical properties of one imidazolium amino acid-based ionic liquid, 1-butyl-3-methylimidazolium glycine. The estimated absorption spectrum successfully rationalizes the unusual and non-negligible absorption band beyond 300 nm for the neat imidazolium-based ionic liquid. The absorption behavior of imidazolium-based ionic liquids is shown to be sensitive to the details of their locally heterogeneous environments. We quantitatively highlight the imidazolium moiety and its various molecular aggregations, rather than the monomeric imidazolium moiety, that are responsible for the absorption characteristics. These results would improve our understanding of the preliminary interplay between structural heterogeneity and optical properties for neat imidazolium-based ionic liquids.

An On-the-Fly Surface-Hopping Program JADE for Nonadiabatic Molecular Dynamics of Polyatomic Systems: Implementation and Applications.

Nonadiabatic dynamics simulations have rapidly become an indispensable tool for understanding ultrafast photochemical processes in complex systems. Here, we present our recently developed on-the-fly nonadiabatic dynamics package, JADE, which allows researchers to perform nonadiabatic excited-state dynamics simulations of polyatomic systems at an all-atomic level. The nonadiabatic dynamics is based on Tully's surface-hopping approach. Currently, several electronic structure methods (CIS, TDHF, TDDFT(RPA/TDA), and ADC(2)) are supported, especially TDDFT, aiming at performing nonadiabatic dynamics on medium- to large-sized molecules. The JADE package has been interfaced with several quantum chemistry codes, including Turbomole, Gaussian, and Gamess (US). To consider environmental effects, the Langevin dynamics was introduced as an easy-to-use scheme into the standard surface-hopping dynamics. The JADE package is mainly written in Fortran for greater numerical performance and Python for flexible interface construction, with the intent of providing open-source, easy-to-use, well-modularized, and intuitive software in the field of simulations of photochemical and photophysical processes. To illustrate the possible applications of the JADE package, we present a few applications of excited-state dynamics for various polyatomic systems, such as the methaniminium cation, fullerene (C20), p-dimethylaminobenzonitrile (DMABN) and its primary amino derivative aminobenzonitrile (ABN), and 10-hydroxybenzo[h]quinoline (10-HBQ).

Water-dependent reaction pathways: an essential factor for the catalysis in HEPD enzyme.

The hydroxyethylphosphonate dioxygenase (HEPD) catalyzes the critical carbon-carbon bond cleavage step in the phosphinothricin (PT) biosynthetic pathway. The experimental research suggests that water molecules play an important role in the catalytic reaction process of HEPD. This work proposes a water involved reaction mechanism where water molecules serve as an oxygen source in the generation of mononuclear nonheme iron oxo complexes. These molecules can take part in the catalytic cycle before the carbon-carbon bond cleavage process. The properties of trapped water molecules are also discussed. Meanwhile, water molecules seem to be responsible for converting the reactive hydroxyl radical group ((-)OH) to the ferric hydroxide (Fe(III)-OH) in a specific way. This converting reaction may prevent the enzyme from damages caused by the hydroxyl radical groups. So, water molecules may serve as biological catalysts just like the work in the heme enzyme P450 StaP. This work could provide a better interpretation on how the intermediates interact with water molecules and a further understanding on the O(18) label experimental evidence in which only a relatively smaller ratio of oxygen atoms in water molecules (∼40%) are incorporated into the final product HMP.

Glycosidic-bond hydrolysis mechanism catalyzed by cellulase Cel7A from Trichoderma reesei: a comprehensive theoretical study by performing MD, QM, and QM/MM calculations.

Cellulase Cel7A from Trichoderma reesei is one of the most abundant and effective cellulases. Structural studies have established that Cel7A is a retaining glycosidase and it can processively hydrolyze cellobiose units from the reducing end of a cellulose chain. Here, to elucidate the mechanism of enzymatic catalysis of cellulase Cel7A, we carried out a multisized level theoretical study by performing MD, QM, and QM/MM calculations. At the accurate level of theory, we showed the mechanism details of the catalytic cycle, which involves the configuration inversion of the anomeric center twice: the first results in the glycosidic bond cleavage and the formation of covalent glycosyl-enzyme intermediate, and the second restores the anomeric carbon to its original configuration. Calculated results have provided detailed structural and energetic information about these two processes, both of which proceed according to a S(N)2-type-like mechanism via loose transition state structures. It is clearly indicated that the glycosidic bond hydrolysis involves the formation of a covalent glycosyl-enzyme intermediate, which has been identified as the minimum on the potential energy surface. At the catalytic active region, hydrogen bond interactions exist throughout the whole process of the catalytic cycle, which are of special importance for stabilizing the glycosyl-enzyme intermediate. The present results provide a clear paradigm of the mechanisms of general glycosidases, which hydrolyze the glycosidic bonds with net retention of the anomeric configuration.