Origin of Enantioselectivity in Engineered Cytochrome c-Catalyzed Carbon-Radical FePP Hydrolysis Revealed Using QM/MM (ABEEM Polarizable Force Field) and MD Simulations.

The origin of highly efficient asymmetric aminohydroxylation of styrene catalyzed by engineered cytochrome c is investigated by the developed Atom-Bond Electronegativity Equalization Method polarizable force field (ABEEM PFF), which is a combined outcome of electronic and steric effects. Model molecules were used to establish the charge parameters of the ABEEM PFF, for which the bond-stretching and angle-bending parameters were obtained by using a combination of modified Seminario and scan methods. The interactions between carbon-radical Fe-porphyrin (FePP) and waters are simulated by molecular dynamics, which shows a clear preference for the pre-R over the pre-S. This preference is attributed to the hydrogen-bond between the mutated 100S and 101P residues as well as van der Waals interactions, enforcing a specific conformation of the carbon-radical FePP complex within the binding pocket. Meanwhile, the hydrogen-bond between water and the nitrogen atom in the active intermediate dictates the stereochemical outcome. Quantum mechanics/molecular mechanics (QM/MM (ABEEM PFF)) and free-energy perturbation calculations elucidate that the 3RTS is characterized by sandwich-like structure among adjacent amino acid residues, which exhibits greater stability than crowed arrangement in 3STS and enables the R enantiomer to form more favorably. Thus, this study provides mechanistic insight into the catalytic reaction of hemoproteins.

Atomic charges in molecules defined by molecular real space partition into atomic subspaces.

Atomic charge (AC), which is the charge distribution of a molecule, is an important property that is closely associated with structures, reactivities, and intra- and inter-molecular interactions among molecules. Several theoretical models or methods can be used to obtain the magnitudes of AC with different characteristics. These models can be classified into fuzzy-atoms models and models partitioning a molecule into individual atoms with sharp boundaries. The first category includes Mulliken, natural population analysis (NPA), Hirshfeld, Merz-Kollman-Singh (MK), CHELPG, the electronegativity equalization method (EEM), the atom-bond electronegativity equalization method (ABEEM), and atomic polar tensor (APT). The second category is derived from quantum chemical topology (QCT) and includes the quantum theory of atoms in molecules (QTAIM) and QCT analysis based on the potential acting on one electron in a molecule (PAEMQCT). Herein, after giving a bird's-eye view of the population methods of the first category, we specifically describe some features of the second category. We only present the basic framework of QCT for obtaining ACs from QTAIM and PAEMQCT and show their important characteristics. QCT establishes the basis of the following chemical concept: a molecule is spatially partitioned into individual atoms with sharp boundaries. The ACs from QTAIM are close to the atomic valence in chemistry, and ACs from PAEMQCT may be practically suitable for modeling intra- and inter-molecular interactions.

Development of a QM/MM(ABEEM) method combined with a polarizable force field to investigate the excision reaction mechanism of damaged thymine.

This paper focuses on the development of a quantum mechanics/molecular mechanics method using the ABEEM polarizable force field (QM/MM(ABEEM) method) to investigate the excision reaction mechanism of damaged thymine. This method does not simply combine the QM method with the polarizable force field. A valence electronegativity piecewise function with the distance between atoms as a variable is introduced to describe the atomic partial charges, and changes greatly during the reaction process. At the same time, the charge transfer effect is treated using the condition of local charge conservation. Compared with the traditional QM/MM method, the QM/MM(ABEEM) method can more accurately simulate the polarization effect and charge transfer effect in the reaction process. Focusing on the controversial problems of the excision of damaged bases, six reaction pathways were designed for monofunctional and difunctional deglycosylation of neutral bases and protonated bases. The results show that the QM/MM(ABEEM) method accurately simulates the polarization effect, charge transfer effect, activation energy and other properties of the reaction process. The process in which the active residue Asp activates the nucleophile H2O to attack the protonated base is the preferred path. The average activation energy and free activation energy of the protonated base are 7.00-14.00 kcal mol-1 lower than that of the neutral base. The study in this paper is helpful to understand the mechanism of repair enzymes in repairing bases.

Development of QM/MM (ABEEM polarizable force field) method to simulate the excision reaction mechanism of damaged cytosine.

DNA damages are regarded as having harmful effects on cell. The base excision repair mechanism combats these effects by removing damaged bases. The deglycosylation mechanism of excising damaged bases by DNA glycosylase and the state of the leaving base have been controversial. The enzymatic reaction of DNA glycosylase to remove the damaged bases involves not only the formation and breaking of chemical bonds, but also complex polarization effect and charge transfer, which cannot be accurately simulated by the QM/MM method combined with the fixed charge force field. This work has developed the ABEEM fluctuating polarizable force field combining with the QM method, that is (QM/MM[ABEEM]), to accurately simulate the proton transfer, charge transfer and the charge distribution. The piecewise function is used as the valence-state electronegativity in the QM/MM (ABEEM) to realize the accurate fitting of the charge distribution in reaction. And the charge transfer is accurately simulated by the local charge conservation conditions. Four deglycosylation mechanisms including the monofunctional and difunctional mechanisms of four neutral and protonated cytosine derivatives are explored. It is confirmed that the monofunctional mechanism of Asp-activated nucleophile water is a better deglycosylation mechanism and the base is protonated before the reaction occurs. Protonization of the base reduced the activation energy by 10.00-17.00 kcal/mol. Asp provides the necessary charge for the reaction, and DNA glycosylase preferentially cleaves ɛC. This work provides a theoretical basis for the research of excising damaged bases by DNA glycosylase.

Refined models of coordination between Al3+/Mg2+ and enzyme in molecular dynamics simulation in terms of ABEEM polarizable force field.

MFX (AlF30, AlF4- and MgF3-) as transition state analogues of phosphoryl transfer enzymes (enzyme-MFX-TSAs) is of great significance for study of the catalytic mechanism of phosphoryl transfer enzymes. Bonded model and non-bonded model based on the ABEEM polarizable force field (ABEEM PFF) are developed and applied to study the coordination of enzyme-MFX-TSAs. The bond stretching of the bond containing metal is simulated by Morse potential energy function, because the change of chemical bond is described more accurately in a large range. The charge distribution of the system is distributed to multiple-charge-sites, including atomic site, σ bond site, π bond site and lone pair electron site. Partial charge can fluctuate according to the surrounding environment and molecular conformation. The reasonable charge distribution of 68 model molecules can be obtained, and the energy minimizations are performed in vacuum. Then, with the same parameters the charge distribution and the charge transfer of four complexes are obtained, and the energy minimization and molecular dynamics simulation in NVT ensemble are carried out in vacuum and explicit water solution. The results verify the correctness, rationality and transferability of the new parameters of ABEEM PFF, and the bonded model simulates more reasonable charge distribution and geometry. The parameters determined in this paper make up the blank of the parameters of MFX and phosophoryl transfer enzymes containing Mg2+. The development of ABEEM PFF provides a refined tool for MFX-TSAs to study the catalytic mechanism of phosphoryl transfer enzymes.

Energetics and J-coupling constants for Ala, Gly, and Val peptides demonstrated using ABEEM polarizable force field in vacuo and an aqueous solution.

The development of an atom-bond electronegativity equalisation method at the σπ-level (ABEEM) polarisable force field (PFF) for peptides is presented. ABEEM PFF utilises a fluctuating charge model to explicitly describe the polarisation effects in an extensive environment. The partial charge of any individual site changes in response to changes in its surroundings. The peptide parameters are derived from ab initio methods in vacuum using a consistent and automatic protocol. By including explicit σ- and π-bond sites and lone pair sites, the anisotropy around an atom has been characterised. The fluctuating charge at each site ensures the distinction between the intrinsic behaviour observed among the various conformations of peptides, as corroborated by the agreement between quantum mechanics (QM) and ABEEM PFF concerning the calculated energy order, charge distribution, locations of minima, and potential energy surface (PES) in vacuo. The energy barriers in the PES have been clearly described using ABEEM PFF, in which a good charge distribution plays a vital role. Molecular dynamic simulations have been performed for short peptides in explicit ABEEM 7P-water boxes to examine their conformational properties in solution. The J-coupling constants obtained using ABEEM PFF are consistent with the experimental nuclear magnetic resonance (NMR) spectra and the influence of the chain length and temperature also investigated. The results demonstrate that the ABEEM PFF method is capable of locating conformations and describing the energetics of peptides with high accuracy and efficiency both in vacuo and an aqueous solution.

Water-Mediated Oxidation of Guanine by a Repair Enzyme: Simulation Using the ABEEM Polarizable Force Field.

The recognition mechanism of oxidative damage in organisms has long been a research hotspot. Water is an important medium in the recognition process, but its specific role remains unknown. There is a need to develop a suitable force field that can adequately describe the electrostatic, hydrogen bond, and other interactions among the molecules in the complex system of the repair enzyme and oxidized base. The developing ABEEM polarizable force field (PFF) has been used to simulate the repaired enzyme hOGG1 and oxidized DNA (PDB ID: 1EBM) in a biological environment, and the corresponding results are better than those of the fixed-charge force fields OPLS/AA and AMBER OL15. 8-Oxo-G is recognized by Gln315 of hOGG1 mainly through hydrogen bonds mediated by continuous exchange of 2 water molecules. Phe319 and Cys253 are stacked on both sides of the π planes of bases to form sandwich structures. The charge polarization effect gives an important signal to drive the exchange of water molecules and maintains the recognition of oxidation bases by enzymes. The mediated main water molecule A and mediated auxiliary water molecule B together pull Gln315 to recognize 8-oxo-G by hydrogen bond interactions. Then, the charge polarization signal of solvent water molecule C with a large absolute charge causes the absolute charge of O atoms in water molecule A or B to increase by approximately 0.2 e, and water molecule A or B leaves Gln315 and 8-oxo-G. The other water molecule and water molecule C synergistically recognize 8-oxo-G with Gln315. Even though the water molecules between Gln315 and 8-oxo-G are removed, the MD simulation results show that water molecules appear between Gln315 and 8-oxo-G in a very short time (<2 ps). The dwell time of each water molecule is approximately 60 ps. The radial distribution function and dwell time support the correctness of the above mechanism. These polarization effects and hydrogen bonding interactions cannot be simulated by a fixed-charge force field.

Dividing the Periodic Box into Subdivisions with Their Surroundings to Accelerate Molecular Dynamics Simulation with High Accuracy.

A major field of current research in chemistry and biology is the development of the tools that enable in situ analysis of complex systems. However, the long-time dynamics simulation for an extremely large system in solution is almost impossible by an all-atom force field combined with an explicit solvent model. The results show that the larger the periodic box is, the closer the properties of the system are to the experimental values. Therefore, how can we carry out simulations for systems that are fast, accurate, and large enough? A method of dividing the periodic box into subdivisions with their surroundings (DBSS) is presented here, and it clearly increases the computation speed without losing accuracy and enables the simulation of extremely large systems by strongly decreasing the dimension of the charge matrix. The DBSS method divides a single periodic box or unit in an extremely large system into several subdivisions with a suitable choice according to atomic coordinates. This method ensures that these subdivisions are always changing and allows the atoms to communicate with each other. Intermolecular communication is important for molecular properties and functions but is not possible with other fragment methods. The partial charges are calculated in each subdivision with an overlapping surrounding used to take hydrogen bond interaction between the subdivisions into account. This is an iterative process because the charge population will be recalculated at intervals during the dynamics simulations. Taking a water system as an example, each subdivision is extended by 4 Å as the surrounding. The computation time scales almost linearly with the size of the system, and the slope is small. MD simulations for several properties have been performed by the ABEEM-DBSS method. The results indicate that the ABEEM-DBSS method can accurately simulate the properties of water system, and the accuracy can reach or approach that of the experimental data or of other water potentials. Interestingly, the properties become closer to the experimental data as the sizes of the periodic box increase, further validating the need for the simulation of a large system and demonstrating the value of the DBSS method.

Systematic Parameterization and Simulation of Boronic Acid-ß-Lactamase Aqueous Solution in Developing the ABEEMσπ Polarizable Force Field.

Boronic acid, an inhibitor of ß-lactamase, has begun to be applied to the treatment of biological infections and tumors. Scientists are working to develop new and more effective boronic acid. Molecular dynamics (MD) simulation provides a powerful auxiliary tool for drug design. However, the current force fields have no boron-related parameters. In this work, an atom-bond electronegativity equalization method at the σπ level (ABEEMσπ) polarizable force field (ABEEMσπ PFF) of boronic acid and ß-lactamase has been developed to determine the potential functions and parameters. The interaction between boron and serine in ß-lactamase is regarded as a bonded mode. The interaction between them is simulated by the Morse potential energy function, which is close to the experimental change of the stretching potential energy in a large range. The potential energy surfaces of the bond length, bond angle, and dihedral angle of boronic acid-ß-lactamase have the same stability point and change trend as M06-2X/6-311G**. For 47 boronic acid-ß-lactamase training molecules, the linear correlation coefficient (R) of the charge distribution between the ABEEMσπ PFF and HF/STO-3G is greater than 0.96. Attributed to the fact that the charge distribution of the ABEEMσπ PFF can fluctuate with the change of geometry and environment, the polarization effect and charge-transfer effect are well reflected. The binding ability of different boronic acids with the same ß-lactamase is different. A total of 10 boronic acid-ß-lactamase model molecules and 10 boronic acid-ß-lactamase and water complexes are simulated. The order of binding energy of five large model molecules calculated by the ABEEMσπ PFF is consistent with that of the MP2 method. The binding energies of boronic acid-ß-lactamase and water complexes are close to those of the MP2 method. The results of MD simulation of five aqueous boronic acid-ß-lactamase complexes in the NVT ensemble verify the rationality of boron-related parameters of the ABEEMσπ PFF, which have a good application prospect. This study lays a solid theoretical foundation for further study of the inhibition of boronic acid on ß-lactamase.

Alterations of fatty acid composition and metabolism in APP/PS1 transgenic mice.

Accumulating evidence suggests that abnormal fatty acid composition is related to the development of Alzheimer's disease (AD). However, there is no consistency in the fatty acid profile and metabolism associated with AD pathogenesis. This study aims to define the characteristics of fatty acid composition and metabolism in AD. Using 6-month-old APP/PS1 transgenic mice with wild-type mice as a control, we examined the serum lipids, brain fatty acid composition, and the expression levels of various genes involved in liver fatty acid ß-oxidation. The results of our study demonstrate that APP/PS1 mice present decreased serum free fatty acids, altered brain fatty acid profiles, and minimal change in liver fatty acid ß-oxidation. Our results suggest that abnormal fatty acid compositions and contents may play potential roles in AD progression. This study provides further evidence for the metabolic basis of AD pathogenesis.

ABEEM/MM OH- Models for OH-(H2O)n Clusters and Aqueous OH-: Structures, Charge Distributions, and Binding Energies.

Based on the atom-bond electronegativity equalization method fused into molecular mechanics (ABEEM/MM), two fluctuating charge models of OH--water system were proposed. The difference between these two models is whether there is charge transfer between OH- and its first-shell water molecules. The structures, charge distributions, charge transfer, and binding energies of the OH-(H2O)n (n = 1-8, 10, 15, 23) clusters were studied by these two ABEEM/MM models, the OPLS/AA force field, the OPLS-SMOOTH/AA force field, and the QM methods. The results demonstrate that two ABEEM/MM models can search out all stable structures just as the QM methods, and the structures and charge distributions agree well with those from the QM calculations. The structures, the charge transfer, and the strength of hydrogen bonds in the first hydration shell are closely related to the coordination number of OH-. Molecular dynamics simulations on the aqueous OH- solution are performed at 298 and 278 K using ABEEM/MM-I model. The MD results show that the populations of three-, four-, and five-coordinated OH- are 29.6%, 67.1%, and 3.4% at 298 K, respectively, and those of two-, three-, four-, and five-coordinated OH- are 10.8%, 44.9%, 39.2%, and 4.9% at 278 K, respectively; the average hydrogen bond lengths and the hydrogen bond angle in the first shell increase with the temperature decreasing.

Partitioning a Molecule into the Atomic Basins and the Resultant Atomic Charges from Quantum Chemical Topology Analysis of the Kohn-Sham Potential.

Quantum chemical topology (QCT) solidifies the chemical basic concepts demonstrating how a molecular system is intrinsically partitioned into its components and what the interaction lines between them are. Here, QCT analysis using a Kohn-Sham one-electron potential (KSpot) in KS equation as a scalar function is initiated and explored, showing KSpot and its resultant electron force lines have novel spatial features which reveal that an atom in a molecule is a spatial basin governed by its nucleus as a 3D-attractor that terminates all the electron force lines defined by the negative gradient of KSpot and that a chemical bond line is just a minimum path of KSpot for the electron motion. Particularly, the atomic charges from this KSpot QCT analysis are moderate and good, having much lower dependence on basis sets chosen for computation. This may provide a platform for the study of molecular structures and properties, intra- and intermolecular electrostatic interaction, energy decomposition, and construction of force field.

Polarizable TIP7P Water Model with Perturbation Charges Evaluated from ABEEM.

A polarizable version of the rigid seven-site (TIP7P) water model with the atom-bond electronegativity equalization method (ABEEM) is proposed. The model uses direct polarization, where an isolated water monomer in the equilibrium geometry is assumed as a reference state and the polarization of the monomer arises from interacting with other molecules as a perturbation of the reference state. The charge on each site of the monomer splits into reference charge and perturbation charge. The perturbation charge arises only because of other reference charges. The interaction of the perturbation charge with other perturbation charges is replaced using polarization scaling to enhance the interaction of perturbation charge with the reference charges of the sites from other molecules. The perturbation charges are updated by evaluating explicit expressions once. This direct polarization is time-reversible because the charge update is independent of the charges in previous simulation steps. A Slater-type damping function moderates the short-range electrostatics to treat charge diffusion. The Ewald method corrects the long-range electrostatics both in the nuclei movement and in electronegativity equalization to diminish the size effect. The water model is parameterized by fitting the ab initio results of water clusters and the experimental results of water monomers and thermodynamic properties for liquid water. Owing to polarizability, the model performs better than the TIP7P model in terms of vaporization enthalpy, isothermal compressibility, and shear viscosity of the liquid phase. It performs better at the melting point of ice but slightly worse under critical conditions than the TIP7P model. Direct polarization has a low time complexity of O(N) and is a good choice for ABEEM to improve its computational efficiency.

Seven-Site Effective Pair Potential for Simulating Liquid Water.

Constant pressure simulations were carried out to construct a new rigid nonpolarizable seven-site water model (TIP7P), which is an effective and efficient version of flexible seven-fluctuating-charge water model. In this model, the positive charges are located on three nuclei and the negative charges disperse on two bond sites at the geometric center of each OH bond and two lone-pair sites along the tetrahedral direction away from the oxygen atom. Our new model performs better than other models in properties, such as radial distribution function, liquid density, thermal expansion coefficient, isothermal compressibility, vaporization enthalpy, isobaric heat capacity, static dielectric constant, self-diffusion coefficient, critical temperature, and density. This model reproduces liquid density and static dielectric constant over the temperatures from 253 to 373 K at 1 atm with the standard deviation of 0.0010 g/cm3 and 1.37 to the experimental data, respectively. The maximum density is 1.0006 g/cm3 at 277 K. The calculated isobaric compressibility presents a minimum at about 310 K close to the experimental value of 319 K. The self-diffusion coefficient agrees the experimental data with the standard deviation of 0.55 × 10-5 cm2/s, although it is not the target property for parameterization. Liquid-vapor phase equilibrium was examined in slab simulations. The evaluated critical temperature and density are 633 K and 0.337 g/cm3 close to the experimental values of 647.096 K and 0.322 g/cm3. This model also presents reasonable vaporization enthalpy and isobaric heat capacity. Based upon good performances mentioned, our new model is a good choice for more accurate investigation to large molecular systems.

Reaction mechanism of NO with hydrolysates of NAMI-A: an MD simulation by combining the QM/MM(ABEEM) with the MD-FEP method.

Nitrosylation reaction mechanisms of the hydrolysates of NAMI-A and hydrolysis reactions of ruthenium nitrosyl complexes were investigated in the triplet state and the singlet state. Activation free energies were calculated by combining the QM/MM(ABEEM) method with free energy perturbation theory, and the explicit solvent environment was simulated by an ABEEMσπ polarizable force field. Our results demonstrate that nitrosylation reactions of the hydrolysates of NAMI-A occur in both the triplet and the singlet states. The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 132.0°-138.2°. However, all the ruthenium nitrosyl complexes at the singlet state show an almost linear Ru-N-O angle. The nitrosylation reaction happens prior to the hydrolysis reaction for the first-step hydrolysates. The activation free energies of the nitrosylation reactions show that the H2 O-NO exchange reaction of [RuCl4 (Im)(H2 O)] in the singlet spin sate is the most likely one. Comparing with the activation free energies of the hydrolysis reactions of the ruthenium nitrosyl complexes, the results indicate that the rate of the DMSO-H2 O exchange reaction of [RuCl3 (NO)(Im)(DMSO)] is faster than that of [RuCl3 (H2 O)(Im)(DMSO)] in both the triplet spin state and the singlet spin state. © 2018 Wiley Periodicals, Inc.

Facile synthesis of bimetallic gold-palladium nanocrystals as effective and durable advanced catalysts for improved electrocatalytic performances of ethylene glycol and glycerol oxidation.

In this work, well-defined bimetallic AuPd alloyed nanocrystals (AuPd NCs) were facilely synthesized by a straightforward and controllable one-step wet-chemical strategy, using a biomolecule (L-hydroxyproline, L-Hyp) as the green stabilizer and the structure-directing agent. Their morphology, size, composition, crystal structures and growth mechanism were investigated by a series of techniques. The synthesized architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic activity, enhanced durability and stability towards ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR) in alkaline electrolytes in comparison with commercial Pd black catalyst.

Theoretical reflections on the structural polymorphism of the oxygen-evolving complex in the S2 state and the correlations to substrate water exchange and water oxidation mechanism in photosynthesis.

The structural polymorphism of the oxygen-evolving complex is of great significance to photosynthetic water oxidation. Employing density functional theory calculations, we have made further advisement on the interconversion mechanism of O5 transfer in the S2 state, mainly focusing on the potentiality of multi-state reactivity and spin transitions. Then, O5 protonation is proven impossible in S2 for irreversibility of the interconversion, which serves as an auxiliary judgment for the protonation state of O5 in S1. Besides, the structural polymorphism could also be archived by alternative mechanisms involving Mn3 ligand exchange, one of which with Mn3(III) makes sense to substrate water exchange in S2, although being irresponsible for the derivations of the observed EPR signals. During the water exchange, high-spin states would prevail to facilitate electron transfer between the ferromagnetically coupled Mn centers. In addition, water exchange in S1 could account for the closed-cubane structure as the initial form entering S2 at cryogenic temperatures. With regard to water oxidation, the structural flexibility and variability in both S2 and S3 guarantee smooth W2-O5 coupling in S4, according to the substrate assignments from water exchange kinetics. Within this theoretical framework, the new XFEL findings on S1-S3 can be readily rationalized. Finally, an alternative mechanistic scenario for OO bond formation with ·OH radical near O4 is presented, followed by water binding to the pivot Mn4(III) from O4 side during S4-S0. This may diversify the substrate sources combined with the Ca channel in water delivery for the forthcoming S-cycle.

The open-cubane oxo-oxyl coupling mechanism dominates photosynthetic oxygen evolution: a comprehensive DFT investigation on O-O bond formation in the S4 state.

The dioxygen formation mechanism of biological water oxidation in nature has long been the focus of argument; many diverse mechanistic hypotheses have been proposed. Based on a recent breakthrough in the resolution of the electronic and structural properties of the oxygen-evolving complex in the S3 state, our density functional theory (DFT) calculations reveal that the open-cubane oxo-oxyl coupling mechanism, whose substrates preferably originate from W2 and O5 in the S2 state, emerges as the best candidate for O-O bond formation in the S4 state. This is justified by the overwhelming energetic superiority of this mechanism over alternative mechanisms in both the isomeric open and closed-cubane forms of the Mn4CaO5 cluster; spin-dependent reactivity rooted in variable magnetic couplings was found to play an essential role. Importantly, this oxygen evolution mechanism is supported by the recent discovery of femtosecond X-ray free electron lasers (XFEL), and the origin of the observed structural changes from the S1 to S3 state has been analyzed. In this view, we corroborate the proposed water binding mechanism during S2-S3 transition and correlate the theoretical models with experimental findings from aspects of substrate selectivity according to water exchange kinetics. This theoretical consequence for native metalloenzymes may serve as a significant guide for improving the design and synthesis of biomimetic materials in the field of photocatalytic water splitting.

Development of the ABEEMσπ Polarization Force Field for Base Pairs with Amino Acid Residue Complexes.

DNA damage caused by oxidized bases can lead to aging and cancer in living beings. Luckily, a repair enzyme is able to repair the oxidized bases. The key step is to accurately recognize the oxidized bases, which mainly rely on complex hydrogen bond interactions. We have calibrated the charge parameters and torsional parameters of the ABEEMσπ polarization force field (ABEEMσπ PFF) to accurately describe the intermolecular and intramolecular interactions. Taking the experiment and quantum chemical method as the benchmark, a series of properties of base pair-amino acid residue systems, DNA and DNA-protein interaction systems were calculated and compared with those of other force fields. We have done a tremendous amount of tasks in testing, calibrations, and analyses. The ABEEMσπ PFF not only explicitly gives the position and the partial charge of lone-pair electrons but also introduces a function kHB to fit special electrostatic interactions in hydrogen bond interaction regions. Therefore, it can accurately simulate the polarization effect and charge transfer of hydrogen bond interactions, especially for charged systems and sulfur-containing systems, such as the binding energy between amino acid and base pairs (24-28 kcal/mol), which is induced by charge transfer. The RMSD of ABEEMσπ PFF is 1.18 kcal/mol, whereas the RMSD of Amber OL15 is 8.21 kcal/mol. The relative positions of the amino acid residue have significantly changed, and the hydrogen bonds were broken when simulated by fixed charge force fields. In addition, owing to refitting the reasonable torsional parameters, the geometric structures optimized by ABEEMσπ PFF were well consistent with those of the M06-2X/6-311++G** method, but the simulations by fixed force fields have a large rotation of methyl and distortion of the plane of the base pair. After extensive MD simulation with four test DNAs and a DNA-protein system, we conclude that ABEEMσπ PFF shows better agreement when compared to experimental structures, which illustrates the reliability of our model and the transferability of the parameters.

How does ammonia bind to the oxygen-evolving complex in the S2 state of photosynthetic water oxidation? Theoretical support and implications for the W1 substitution mechanism.

Ammonia as a water analogue can bind to the Mn4CaO5 cluster of the oxygen-evolving complex in concomitance with ligand substitution and underlying structural transformation. On account of current controversies of the binding site and the absence of the viewpoint of reactivity and mechanistic proofs, we have investigated three modes of NH3 binding based on our elaborations of the possible reaction mechanisms, in correspondence with experimental observation for the NH3-altered g ≈ 2.0 EPR multiline signal. Broken-symmetry density functional theory was employed to construct all the spin surfaces. As a result, we rule out the O5 substitution strategy owing to the impenetrable free energy barrier exceeding 30 kcal mol-1, and alternative routes to destroy the O5 bridge are also blocked. The W1 substitution mechanism is shown to be quite facile, with the barrier not above 11.4 kcal mol-1. For the Mn4 addition scheme, the 'redox switch mechanism' was not implemented by our model, and the effective ways found render 15-22 kcal mol-1 energetic disadvantage by contrast. Consequently, it is strongly in favor of the W1 substitution mechanism for its overwhelming superiority in reactivity, reaching a consensus with the new pulse EPR conclusion. Then, we point out that ammonia departure occurs in the S4' state, with the O-O bonding but unreleased molecular O2. In the meantime, we propose two alternative channels for water binding in the S0' state and expound the significance to substrate selectivity. Ultimately, implications for the mechanism of O-O bond formation are discussed and all the remaining options are listed for future explorations.