A porphyrin-based molecular cage guided by designed local-electric field is highly selective and efficient.

The present work outlines a general methodology for designing efficient catalytic machineries that can easily be tweaked to meet the demands of the target reactions. This work utilizes a principle of the designed local electric field (LEF) as the driver for an efficient catalyst. It is demonstrated that by tweaking the LEF, we can catalyze the desired hydroxylation products with enantioselectivity that can be changed at will. Using computation tools, we caged a synthetic analog of heme porphyrin (HM1) and investigated the pharmaceutically relevant conversion of tetralin to tetralol, inside the modified supramolecular cage. The QM/MM calculations demonstrate a resulting catalytic efficiency with virtually absolute R-selectivity for the tetralin hydroxylation. Our calculations show that the LEF of the supramolecular cage and HM1 exert a strong electric field along the Fe-O reaction axis, which is the main driving force for enhanced reactivity. At the same time, the supramolecular cage applies a lateral LEF that regulates the enantioselectivity. We further demonstrate that swapping the charged/polar substitution in the supramolecular cage switches the lateral LEF which changes the enantioselectivity of hydroxylation from R to S.

Electro-Freezing of Supercooled Water Is Induced by Hydrated Al3+ and Mg2+ Ions: Experimental and Theoretical Studies.

This work reports that the octahedral hydrated Al3+ and Mg2+ ions operate within electrolytic cells as kosmotropic (long-range order-making) "ice makers" of supercooled water (SCW). 10-5 M solutions of hydrated Al3+ and Mg2+ ions each trigger, near the cathode (-20 ± 5 V), electro-freezing of SCW at -4 °C. The hydrated Al3+ ions do so with 100% efficiency, whereas the Mg2+ ions induce icing with 40% efficiency. In contrast, hydrated Na+ ions, under the same experimental conditions, do not induce icing differently than pure water. As such, our study shows that the role played by Al3+ and Mg2+ ions in water electro-freezing is impacted by two synchronous effects: (1) a geometric effect due to the octahedral packing of the coordinated water molecules around the metallic ions, and (2) the degree of polarization which these two ions induce and thereby acidify the coordinated water molecules, which in turn imparts them with an ice-like structure. Long-duration molecular dynamics (MD) simulations of the Al3+ and Mg2+ indeed reveal the formation of "ice-like" hexagons in the vicinity of these ions. Furthermore, the MD shows that these hexagons and the electric fields of the coordinate water molecules give rise to ultimate icing. As such, the MD simulations provide a rational explanation for the order-making properties of these ions during electro-freezing.

How Can Static and Oscillating Electric Fields Serve in Decomposing Alzheimer's and Other Senile Plaques?

Alzheimer's disease is one of the most common neurodegenerative conditions, which are ascribed to extracellular accumulation of ß-amyloid peptides into plaques. This phenomenon seems to typify other related neurodegenerative diseases. The present study uses classical molecular-dynamics simulations to decipher the aggregation-disintegration behavior of ß-amyloid peptide plaques in the presence of static and oscillating oriented external electric fields (OEEFs). A long-term disintegration of such plaques is highly desirable since this may improve the prospects of therapeutic treatments of Alzheimer's disease and of other neurodegenerative diseases typified by senile plaques. Our study illustrates the spontaneous aggregation of the ß-amyloid, its prevention and breakdown when OEEF is applied, and the fate of the broken aggregate when the OEEF is removed. Notably, we demonstrate that the usage of an oscillating OEEF on ß-amyloid aggregates appears to lead to an irreversible disintegration. Insight is provided into the root causes of the various modes of aggregation, as well as into the different fates of OEEF-induced disintegration in oscillating vs static fields. Finally, our simulation results are compared to the well-established TTFields and the Deep Brain Stimulation (DBS) therapies, which are currently used options for treatments of Alzheimer's disease and other related neurodegenerative diseases.

Computations reveal a crucial role of an aromatic dyad in the catalytic function of plant cytochrome P450 mint superfamily.

Enzymes are highly specific for their native functions, however with advances in bioengineering tools such as directed evolution, several enzymes are being repurposed for the secondary function of contemporary significance(Khersonsky and Tawfik, 2010 [1]). Due to the functional versatility, the Cytochrome P450 (CYP450) superfamily has become the ideal scaffold for such bioengineering. In the current study, using MD (molecular dynamics) simulations and hybrid QM/MM (Quantum mechanics/molecular mechanics) calculations, we have studied the mechanism of spontaneous emergence of a secondary function due to a single site mutation in two plant CYP450 enzymes from the mint family. The MD simulations of WT (wild type) CYP71D18 and CYP71D13 enzymes and their variants show a crucial gating mechanism by aromatic dyad formed by Phe121 and Phe363 which regulates the substrate recognition. The QM/MM calculations reveal that the hydroxylation reactions at C3 and C6 positions in WT CYP71D18 and CYP71D13 enzymes as well as their variants follow a hydrogen atom transfer (HAT) followed by a single electron transfer (SET) mechanism, which is different from the typical rebound mechanism shown by most of the CYP450 enzymes.

Local Electric Fields Dictate Function: The Different Product Selectivities Observed for Fatty Acid Oxidation by Two Deceptively Very Similar P450-Peroxygenases OleT and BSß.

Cytochrome P450 peroxygenases use hydrogen peroxide to hydroxylate long-chain fatty acids by bypassing the use of O2 and a redox partner. Among the peroxygenases, P450OleT uniquely performs decarboxylation of fatty acids and production of terminal olefins. This route taken by P450OleT is intriguing, and its importance is augmented by the practical importance of olefin production. As such, this mechanistic choice merits elucidation. To address this puzzle, we use hybrid QM/MM calculations and MD simulations for the OleT enzyme as well as for the structurally analogous enzyme, P450BSß. The study of P450OleT reveals that the protonated His85 in the wild-type P450OleT plays a crucial role in steering decarboxylation activity by stabilizing the corresponding hydroxoiron(IV) intermediate (Cpd II). In contrast, for P450BSß in which Q85 replaces H85, the respective Cpd II species is unstable and it reacts readily with the substrate radical by rebound, producing hydroxylation products. As shown, this single-site difference creates in P450OleT a local electric field (LEF), which is significantly higher than that in P450BSß. In turn, these LEF differences are responsible for the different stabilities of the respective Cpd II/radical intermediates and hence for different functions of the two enzymes. P450BSß uses the common rebound mechanism and leads to hydroxylation, whereas P450OleT proceeds via decarboxylation and generates terminal olefins. Olefin production projects the power of a single residue to alter the LEF and the enzyme's function.

MD simulations and QM/MM calculations reveal the key mechanistic elements which are responsible for the efficient C-H amination reaction performed by a bioengineered P450 enzyme.

An enzyme which is capable of catalyzing C-H amination reactions is considered to be a dream tool for chemists due to its pharmaceutical potential and greener approach. Recently, the Arnold group achieved this feat using an engineered CYP411 enzyme, which further undergoes a random directed evolution which increases its efficiency and selectivity. The present study provides mechanistic insight and the root cause of the success of these mutations to enhance the reactivity and selectivity of the mutant enzyme. This is achieved by means of comprehensive MD simulations and hybrid QM/MM calculations. The study shows that the efficient C-H amination by the engineered CYP411 is a combined outcome of electronic and steric effects. The mutation of the axial cysteine ligand to serine relays electron density to the Fe ion in the heme, and thereby enhances the bonding capability of the heme-iron to the nitrogen atom of the tosyl azide. In comparison, the native cysteine-ligated P450 cannot bind the tosyl azide. Additionally, the A78V and A82L mutations in P411 provide 'bulk' to the active site which increases the enantioselectivity via a steric effect. At the same time, the QM/MM calculations elucidate the C-H amination by the iron nitrenoid, revealing a mechanism analogous to Compound I in the native C-H hydroxylation by P450.

Solvent Organization and Rate Regulation of a Menshutkin Reaction by Oriented External Electric Fields are Revealed by Combined MD and QM/MM Calculations.

When and how do external electric fields (EEFs) lead to catalysis in the presence of a (polar or nonpolar) solvent? This is the question that is addressed here using a combination of molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical calculations with EEF, and quantum mechanical/(local) electric field calculations. The paper focuses on a model reaction, the Menshutkin reaction between CH3I and pyridine in three solvents of varying polarity. Using MD simulations, we find that the EEF causes the solvent to undergo organization; the solvent molecules gradually align with the applied field as the field strength increases. The collective orientation of the solvent molecules modifies the electrostatic environment around the Menshutkin species and induces a global electric field pointing in the opposite direction of the applied EEF. The combination of these two entangled effects leads to partial or complete screening of the EEF, with the extent of screening being proportional to the polarity/polarizability of the solvent. Nevertheless, we find that catalysis of the Menshutkin reaction inevitably emerges once the EEF exceeds the opposing field of the organizing solvent, i.e., once polarization of the Menshutkin complex is observed to set in. Overall, our analysis provides a lucid and pictorial interpretation of the behavior of solutions in the presence of EEFs and indicates that EEF-mediated catalysis should, in principle, be feasible in bulk setups, especially for nonpolar and mildly polar solvents. By application of the charge-transfer paradigm, it is shown that the emergence of OEEF catalysis in solution can be generalized to other reactions as well.