Highly Ordered Co-Assembly of Bisurea Functionalized Molecular Switches at the Solid-Liquid Interface.

Immobilization of stimulus-responsive systems on solid surfaces is beneficial for controlled signal transmission and adaptive behavior while allowing the characterization of the functional interface with high sensitivity and high spatial resolution. Positioning of the stimuli-responsive units with nanometer-scale precision across the adaptive surface remains one of the bottlenecks in the extraction of cooperative function. Nanoscale organization, cooperativity, and amplification remain key challenges in bridging the molecular and the macroscopic worlds. Here we report on the design, synthesis, and scanning tunneling microscopy (STM) characterization of overcrowded alkene photoswitches merged in self-assembled networks physisorbed at the solid-liquid interface. A detailed anchoring strategy that ensures appropriate orientation of the switches with respect to the solid surface through the use of bis-urea groups is presented. We implement a co-assembly strategy that enables the merging of the photoswitches within physisorbed monolayers of structurally similar 'spacer' molecules. The self-assembly of the individual components and the co-assemblies was examined in detail using (sub)molecular resolution STM which confirms the robust immobilization and controlled orientation of the photoswitches within the spacer monolayers. The experimental STM data is supported by detailed molecular mechanics (MM) simulations. Different designs of the switches and the spacers were investigated which allowed us to formulate guidelines that enable the precise organization of the photoswitches in crystalline physisorbed self-assembled molecular networks.

Exploring the selectivity of cytochrome P450 for enhanced novel anticancer agent synthesis.

Cytochrome P450 monooxygenases are an extensive and unique class of enzymes, which can regio- and stereo-selectively functionalise hydrocarbons by way of oxidation reactions. These enzymes are naturally occurring but have also been extensively applied in a synthesis context, where they are used as efficient biocatalysts. Recently, a biosynthetic pathway where a cytochrome P450 monooxygenase catalyses a critical step of the pathway was uncovered, leading to the production of a number of products that display high antitumour potency. In this work, we use computational techniques to gain insight into the factors that determine the relative yields of the different products. We use conformational search algorithms to understand the substrate stereochemistry. On a machine-learned 3D protein structure, we use molecular docking to obtain a library of favourable poses for substrate-protein interaction. With molecular dynamics, we investigate the most favourable poses for reactivity on a molecular level, allowing us to investigate which protein-substrate interactions favour a given product and thus gain insight into the product selectivity.

Exploration of biochemical reactivity with a QM/MM growing string method.

In this work, we have implemented the single-ended growing string method using a hybrid internal/Cartesian coordinate scheme within our in-house QM/MM package, QoMMMa, representing the first implementation of the growing string method in the QM/MM framework. The goal of the implementation was to facilitate generation of QM/MM reaction pathways with minimal user input, and also to improve the quality of the pathways generated as compared to the widely used adiabatic mapping approach. We have validated the algorithm against a reaction which has been studied extensively in previous computational investigations - the Claisen rearrangement catalysed by chorismate mutase. The nature of the transition state and the height of the barrier was predicted well using our algorithm, where more than 88% of the pathways generated were deemed to be of production quality. Directly compared to using adiabatic mapping, we found that while our QM/MM single-ended growing string method is slightly less efficient, it readily produces reaction pathways with fewer discontinuites and thus minimises the need for involved remapping of unsatisfactory energy profiles.

Gaseous inhibition of the transsulfuration pathway by cystathionine ß-synthase.

The transsulfuration pathway plays a key role in mammals for maintaining the balance between cysteine and homocysteine, whose concentrations are critical in several biochemical processes. Human cystathionine ß-synthase is a heme-containing, pyridoxal 5'-phosphate (PLP)-dependent enzyme found in this pathway. The heme group does not participate directly in catalysis, but has a regulatory function, whereby CO or NO binding inhibits the PLP-dependent reactions. In this study, we explore the detailed structural changes responsible for inhibition using quantum chemical calculations to validate the experimentally observed bonding patterns associated with heme CO and NO binding and molecular dynamics simulations to explore the medium-range structural changes triggered by gas binding and propagating to the PLP active site, which is more than 20 Å distant from the heme group. Our results support a previously proposed mechanical signaling model, whereby the cysteine decoordination associated with gas ligand binding leads to breaking of a hydrogen bond with an arginine residue on a neighbouring helix. In turn, this leads to a shift in position of the helix, and hence also of the PLP cofactor, ultimately disrupting a key hydrogen bond that stabilizes the PLP in its catalytically active form.

The Fe-MAN Challenge: Ferrates-Microkinetic Assessment of Numerical Quantum Chemistry.

Organometallic species, such as organoferrate ions, are prototypical nucleophiles prone to reacting with a wide range of electrophiles, including proton donors. In solution, the operation of dynamic equilibria and the simultaneous presence of several organometallic species severely complicate the analysis of these fundamentally important reactions. This can be overcome by gas-phase experiments on mass-selected ions, which allow for the determination of the microscopic reactivity of the target species. In this contribution, we focus on the reactivity of a series of trisarylferrate complexes toward 2,2,2-trifluoroethanol and 2,2-difluoroethanol. By means of mass-spectrometric measurements, we determined the experimental bimolecular rate constants kexp of the gas-phase protolysis reactions of the trisarylferrate anions FePh3- and FeMes3- with the aforementioned acids. Based on these experiments, we carried out a dual blind challenge, inviting theoretical groups to submit their best predictions for the activation barriers and/or theoretical rate constants ktheo. This provides a unique opportunity to evaluate different computational protocols under minimal bias and sets the stage for further benchmarking of quantum chemical methods and data-driven approaches in the future.

An automated method for graph-based chemical space exploration and transition state finding.

Algorithms that automatically explore the chemical space have been limited to chemical systems with a low number of atoms due to expensive involved quantum calculations and the large amount of possible reaction pathways. The method described here presents a novel solution to the problem of chemical exploration by generating reaction networks with heuristics based on chemical theory. First, a second version of the reaction network is determined through molecular graph transformations acting upon functional groups of the reacting. Only transformations that break two chemical bonds and form two new ones are considered, leading to a significant performance enhancement compared to previously presented algorithm. Second, energy barriers for this reaction network are estimated through quantum chemical calculations by a growing string method, which can also identify non-octet species missed during the previous step and further define the reaction network. The proposed algorithm has been successfully applied to five different chemical reactions, in all cases identifying the most important reaction pathways.

Machine Learning Representations of the Three Lowest Adiabatic Electronic Potential Energy Surfaces for the ArH2+ Reactive System.

In this work, we present Gaussian process regression machine learning representations of the three lowest coupled 2A' adiabatic electronic potential energy surfaces of the ArH2+ reactive system in full dimensionality. Additionally, the nonadiabatic coupling matrix elements were calculated. These adiabatic potentials and their nonadiabatic couplings are necessary ingredients in the theoretical investigation of the nonadiabatic reaction dynamics of the Ar + H2+ → ArH+ + H and Ar+ + H2 → ArH+ + H reactions, as well as the competing charge transfer process, Ar + H2+↔ Ar+ + H2. Accurate ab initio electronic structure calculations (ic-MRCI+Q/aug-cc-pVQZ), whereby the effect of spin-orbit coupling in Ar+ has been accounted for through the state interaction method, serve as input for the machine learning training process. The potential energy surfaces are fitted with high accuracies, with root-mean-square errors on the order of 10-7 eV for the three surfaces, which meet the requirements for chemical dynamics at low temperature. It was found that quite a large number of training points (of the order of 5000 ab initio points) are needed in order to achieve these accuracies due to the complex topography of these electronic surfaces.

The Mechanism of Biochemical NO-Sensing: Insights from Computational Chemistry.

The binding of small gas molecules such as NO and CO plays a major role in the signaling routes of the human body. The sole NO-receptor in humans is soluble guanylyl cyclase (sGC) - a histidine-ligated heme protein, which, upon NO binding, activates a downstream signaling cascade. Impairment of NO-signaling is linked, among others, to cardiovascular and inflammatory diseases. In the present work, we use a combination of theoretical tools such as MD simulations, high-level quantum chemical calculations and hybrid QM/MM methods to address various aspects of NO binding and to elucidate the most likely reaction paths and the potential intermediates of the reaction. As a model system, the H-NOX protein from Shewanella oneidensis (So H-NOX) homologous to the NO-binding domain of sGC is used. The signaling route is predicted to involve NO binding to form a six-coordinate intermediate heme-NO complex, followed by relatively facile His decoordination yielding a five-coordinate adduct with NO on the distal side with possible isomerization to the proximal side through binding of a second NO and release of the first one. MD simulations show that the His sidechain can quite easily rotate outward into solvent, with this motion being accompanied in our simulations by shifts in helix positions that are consistent with this decoordination leading to significant conformational change in the protein.

Microscopic Reactivity of Phenylferrate Ions toward Organyl Halides.

Despite its practical importance, organoiron chemistry remains poorly understood due to its mechanistic complexity. Here, we focus on the oxidative addition of organyl halides to phenylferrate anions in the gas phase. By mass-selecting individual phenylferrate anions, we can determine the effect of the oxidation state, the ligation, and the nuclearity of the iron complex on its reactions with a series of organyl halides RX. We find that Ph2 Fe(I)- and other low-valent ferrates are more reactive than Ph3 Fe(II)- ; Ph4 Fe(III)- is inert. The coordination of a PPh3 ligand or the presence of a second iron center lower the reactivity. Besides direct cross-coupling reactions resulting in the formation of RPh, we also observe the abstraction of halogen atoms. This reaction channel shows the readiness of organoiron species to undergo radical-type processes. Complementary DFT calculations afford further insight and rationalize the high reactivity of the Ph2 Fe(I)- complex by the exothermicity of the oxidative addition and the low barriers associated with this reaction step. At the same time, they point to the importance of changes of the spin state in the reactions of Ph3 Fe(II)- .

Effect of solvent motions on the dynamics of the Diels-Alder reaction.

How solvent motions affect the dynamics of chemical reactions in which the solute undergoes a substantial shape change is a fundamental but elusive issue. This work utilizes reactive simulation and Grote-Hynes theory to explore the effect of solvent motions on the dynamics of the Diels-Alder reaction (in the reverse direction, this reaction involves very substantial solute expansion) in aprotic solvents. The results reveal that the solvent environment is not sufficiently constraining to influence transition state passage dynamics, with the calculated transmission coefficients being close to unity. Even when solvent motions are suppressed or artificially slowed down, the solvent only affects the reaction dynamics in the transition state region to a very small extent. The only notable effect of solvent occurs far from the transition state region and corresponds to caging of the reactants within the reactant well.

On the Use of Normalized Metrics for Density Sensitivity Analysis in DFT.

In the past years, there has been a discussion about how the errors in density functional theory might be related to errors in the self-consistent densities obtained from different density functional approximations. This, in turn, brings up the discussion about the different ways in which we can measure such errors and develop metrics that assess the sensitivity of calculated energies to changes in the density. It is important to realize that there cannot be a unique metric in order to look at this density sensitivity, simultaneously needing size-extensive and size-intensive metrics. In this study, we report two metrics that are widely applicable to any density functional approximation. We also show how they can be used to classify different chemical systems of interest with respect to their sensitivity to small variations in the density.

Spin-Forbidden Reactivity of Transition Metal Oxo Species: Exploring the Potential Energy Surfaces.

Spin-forbidden reactions are frequently encountered when transition metal oxo species are involved, particularly in oxygen transfer reactivity. The computational study of such reactions is challenging, because reactants and products are located on different spin potential energy surfaces (PESs). One possible approach to describe these reactions is the so-called minimum energy crossing point (MECP) between the diabatic reactants and products PESs. Alternatively, inclusion of spin-orbit coupling (SOC) effects allows to locate a saddle point on a single adiabatic PES (TS SOC). The TS SOC approach is rarely applied because of its high computational cost. Recently evidence for a TS SOC impact on significantly lowering the activation barrier in dioxygen addition to a carbene-gold(I)-hydride complex reaction (Chem. Sci. 2016, 7, 7034-7039) or even on predicting a qualitatively different reaction mechanism in mercury methylation by cobalt corrinoid (Angew. Chem. Int. Ed. 2016, 55, 11503-11506) has been put forward. Using MECP and TS SOC approaches a systematic analysis is provided here of three prototypical transition metal oxo spin-forbidden processes to investigate their implications on reactivity. Cycloaddition of ethylene to chromyl chloride (CrO2 Cl2 +C2 H4 ), iron oxide cation insertion into the hydrogen molecule (FeO+ +H2 ) and H-abstraction from toluene by a MnV -oxo-porphyrin cation (MnOP(H2 O)+ +C6 H5 CH3 ) are case studies. For all these processes the MECP and TS SOC results are compared, which show that the spin-forbidden reactivity of transition metal oxo species can be safely described by a MECP approach, at least for the first-row transition metals investigated here, where the spin-orbit coupling is relatively weak. However, for the Mn-oxo reactivity, the MECP and TS SOC have been found to be crucial for a correct description of the reaction mechanism. In particular, the TS SOC approach allows to straightforwardly explore detailed features of the adiabatic potential energy surface which in principle could affect the overall reaction rate in cases where the involved diabatic PESs are tricky.

Energetics of non-heme iron reactivity: can ab initio calculations provide the right answer?

We use a variety of computational methods to characterize and compare the hydrogen atom transfer (HAT) and epoxidation reaction pathways for oxidation of cyclohexene by an iron(iv)-oxo complex. Previous B3LYP calculations have led to predictions that both alcohol (from the HAT route) and epoxide should be formed in similar amounts, which was not in agreement with experiment where only the HAT product was observed. We show here that ab initio calculations which can take both static and dynamic correlation into account are needed to explain the experimentally observed dominance of the HAT process. Since these systems do not have very strong multireference character we have also tested different flavours of local coupled cluster methods. We suggest that further improvements are necessary before they can provide highly accurate results for these systems.

Mechanism of the highly effective peptide bond hydrolysis by MOF-808 catalyst under biologically relevant conditions.

Efficient and selective hydrolysis of inert peptide bonds is of paramount importance. MOF-808, a metal-organic framework based on Zr6 nodes, can hydrolyze peptide bonds efficiently under biologically relevant conditions. However, the details of the catalyst structure and of the underlying catalytic reaction mechanism are challenging to establish. By means of DFT calculations we first investigate the speciation of the Zr6 nodes and identify the nature of ligands that bind to the Zr6O8H4-x core in aqueous conditions. The core is predicted to strongly prefer a Zr6O8H4 protonation state and to be predominantly decorated by bridging formate ligands, giving Zr6(µ3-O)4(µ3-OH)4(BTC)2(HCOO)6 and Zr6(µ3-O)4(µ3-OH)4(BTC)2(HCOO)5(OH)(H2O) as the most favorable structures at physiological pH. The GlyGly peptide can bind MOF in several different ways, with the preferred structure involving coordination through the terminal carboxylate analogously to the binding mode of formate ligand. The pre-reactive binding mode in which the amide carbonyl oxygen coordinates the metal core lies 7 kcal higher in free energy. The preferred reaction pathway is predicted to have two close-lying transition states, either of which could be the rate-determining step: nucleophilic attack on the amide carbon atom and C-N bond breaking, with calculated relative free energies of 31 and 32 kcal mol-1, respectively. Replacement of formate by water and hydroxide at the Zr6 node is predicted to be possible, but does not appear to play a role in the hydrolysis mechanism.

Assembly-line synthesis of organic molecules with tailored shapes.

Molecular 'assembly lines', in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes-helical or linear-depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Computational Chemistry and Non-noble Metal-catalyzed Cross-coupling Reaction Mechanisms.

This short overview discusses the contribution that computational methods can make to the study of reaction mechanisms in non-noble-metal-catalyzed cross-coupling reactions. The differences between such reactions and those catalyzed by more traditional noble metals are emphasized, together with the challenge this poses to computation.

Chemical Mimics of Aspartate-Directed Proteases: Predictive and Strictly Specific Hydrolysis of a Globular Protein at Asp-X Sequence Promoted by Polyoxometalate Complexes Rationalized by a Combined Experimental and Theoretical Approach.

Creating efficient and residue-directed artificial proteases is a challenging task due to the extreme inertness of the peptide bond, combined with the difficulty of achieving specific interactions between the catalysts and the protein side chains. Herein we report strictly site-selective hydrolysis of a multi-subunit globular protein, hemoglobin (Hb) from bovine blood, by a range of ZrIV -substituted polyoxometalates (Zr-POMs) in mildly acidic and physiological pH solutions. Among 570 peptide bonds in Hb, selective cleavage was observed at only eleven sites, each occurring at Asp-X peptide bonds located in the positive patches on the protein surface. The molecular origins of the observed Asp-X selectivity were rationalized by means of molecular docking, DFT-based binding, and mechanistic studies on model peptides. The proposed mechanism of hydrolysis involves coordination of the amide oxygen to ZrIV followed by a direct nucleophilic attack of the side chain carboxylate group on the C-terminal amide carbon atom with formation of a cyclic anhydride, which is further hydrolyzed to give the reaction products. The activation energy for the cleavage of the structurally related Glu-X sequence compared to Asp-X was calculated to be higher by 1.4 kcal mol-1 , which corresponds to a difference of about one order of magnitude in the rates of hydrolysis. The higher activation energy is attributed to the higher strain present in the six-membered ring of glutaric anhydride (Glu-X), as compared to the five-membered ring of the succinic anhydride (Asp-X) intermediate. Similarly, the cleavage at X-Asp and X-Glu bonds are predicted to be kinetically less likely as the corresponding activation energies were 6 kcal mol-1 higher, explaining the experimentally observed selectivity. The synergy between the negatively charged polyoxometalate cluster, which binds at positive patches on protein surfaces, and selective activation of Asp-X peptide bonds located in these regions by ZrIV ions, results in a novel class of artificial proteases with aspartate-directed reactivity, which is very rare among naturally occurring proteases.

A New Insight into the Stereoelectronic Control of the Pd0 -Catalyzed Allylic Substitution: Application for the Synthesis of Multisubstituted Pyran-2-ones via an Unusual 1,3-Transposition.

Pyran-2-ones 3 undergo a novel Pd0 -catalyzed 1,3-rearrangement to afford isomers 6. The reaction proceeds via an η2 -Pd complex, the pyramidalization of which (confirmed by quantum chemistry calculations) offers a favorable antiperiplanar alignment of the Pd-C and allylic C-O bonds (C), thus allowing the formation of an η3 -Pd intermediate. Subsequent rotation and rate-limiting recombination with the carboxylate arm then gives isomeric pyran-2-ones 6. The calculated free energies reproduce the observed kinetics semi-quantitatively.

Suzuki-Miyaura coupling revisited: an integrated computational study.

New density functional theory (DFT) computations are reported concerning the mechanism of the Suzuki-Miyaura cross-coupling reaction of aryl halides and aryl boronic acids catalyzed by palladium phosphine complexes. The calculations are aimed at refining the understanding of the overall catalytic mechanism using state of the art theoretical approaches (including, for the first time, an attempt to describe the Gibbs energy of the reactant base in a realistic way). New experimental results (Thomas and Denmark, Science, 2016, 352, 329-332) concerning pre-transmetallation intermediates with a Pd-O-B linkage provide an invaluable benchmark to test the accuracy of the calculations. The calculations show that bottlenecks to catalysis associated with oxidative addition, X-to-O substitution at Pd, and transmetallation can lie close in energy.

The effect of coordination of alkanes, Xe and CO2 (η1-OCO) on changes in spin state and reactivity in organometallic chemistry: a combined experimental and theoretical study of the photochemistry of CpMn(CO)3.

A combined experimental and theoretical study is presented of several ligand addition reactions of the triplet fragment 3CpMn(CO)2 formed upon photolysis of CpMn(CO)3. Experimental data are provided for reactions in n-heptane and perfluoromethylcyclohexane (PFMCH), as well as in PFMCH doped with C2H6, Xe and CO2. In PFMCH we find that the conversion of 3CpMn(CO)2 to 1CpMn(CO)2(PFMCH) is much slower (τ = 18 (±3) ns) than the corresponding reactions in conventional alkanes (τ = 111 (±10) ps). We measure the effect of the coordination ability by doping PFMCH with alkane, Xe and CO2; these doped ligands form the corresponding singlet adducts with significantly variable formation rates. The reactivity as measured by the addition timescale follows the order 1CpMn(CO)2(C5H10) (τ = 270 (±10) ps) > 1CpMn(CO)2Xe (τ = 3.9 (±0.4) ns) ∼ 1CpMn(CO)2(CO2) (τ = 4.7 (±0.5) ns) > 1CpMn(CO)2(C7F14) (τ = 18 (±3) ns). Electronic structure theory calculations of the singlet and triplet potential energy surfaces and of their intersections, together with non-adiabatic statistical rate theory, reproduce the observed rates semi-quantitatively. It is shown that triplet adducts of the ligand and 3CpMn(CO)2 play a role in the kinetics, and account for the variable timescales observed experimentally.