The influence of model building schemes and molecular dynamics sampling on QM-cluster models: the chorismate mutase case study.

Most QM-cluster models of enzymes are constructed based on X-ray crystal structures, which limits comparison to in vivo structure and mechanism. The active site of chorismate mutase from Bacillus subtilis and the enzymatic transformation of chorismate to prephenate is used as a case study to guide construction of QM-cluster models built first from the X-ray crystal structure, then from molecular dynamics (MD) simulation snapshots. The Residue Interaction Network ResidUe Selector (RINRUS) software toolkit, developed by our group to simplify and automate the construction of QM-cluster models, is expanded to handle MD to QM-cluster model workflows. Several options, some employing novel topological clustering from residue interaction network (RIN) information, are evaluated for generating conformational clustering from MD simulation. RINRUS then generates a statistical thermodynamic framework for QM-cluster modeling of the chorismate mutase mechanism via refining 250 MD frames with density functional theory (DFT). The 250 QM-cluster models sampled provide a mean ΔG‡ of 10.3 ± 2.6 kcal mol-1 compared to the experimental value of 15.4 kcal mol-1 at 25 °C. While the difference between theory and experiment is consequential, the level of theory used is modest and therefore "chemical" accuracy is unexpected. More important are the comparisons made between QM-cluster models designed from the X-ray crystal structure versus those from MD frames. The large variations in kinetic and thermodynamic properties arise from geometric changes in the ensemble of QM-cluster models, rather from the composition of the QM-cluster models or from the active site-solvent interface. The findings open the way for further quantitative and reproducible calibration in the field of computational enzymology using the model construction framework afforded with the RINRUS software toolkit.

Donor Ability of Bisphosphinemonoxide Ligands Relevant to Late-Metal Olefin Polymerization Catalysis.

Late-transition-metal catalysts for polymerization of olefins have drawn a significant amount of attention owing to their ability to tolerate and incorporate polar comonomers. However, a systematic way to experimentally quantify the electronic properties of the ligands used in these systems has not been developed. Quantified ligand parameters will allow for the rational design of tailored polymerization catalysts, which would target specific polymer properties. We report a series of platinum complexes bearing bisphosphinemonoxide ligands, which resemble those used in the polymerization catalysts of Nozaki and Chen. Their electronic properties are investigated experimentally, and trends are rationalized by using computed spectral properties. Benchmarking computational data with known experimental parameters further enhances the utility of both methods for determining optimal ligands for catalytic application.

The Glycine N-Methyltransferase Case Study: Another Challenge for QM-Cluster Models?

The methyl transfer reaction between SAM and glycine catalyzed by glycine N-methyltransferase (GNMT) was examined using QM-cluster models generated by Residue Interaction Network ResidUe Selector (RINRUS). RINRUS is a Python-based tool that can build QM-cluster models with rules-based processing of the active site residue interaction network. This way of enzyme model-building allows quantitative analysis of residue and fragment contributions to kinetic and thermodynamic properties of the enzyme. Many residue fragments are important for the GNMT catalytic reaction, such as Gly137, Asn138, and Arg175, which interact with the glycine substrate, and Trp30, Asp85, and Tyr242, which interact with the SAM cofactor. Our study shows that active site fragments that interact with the glycine substrate and the SAM cofactor must both be included in the QM-cluster models. Even though the proposed mechanism is a simple one-step reaction, GNMT may be a rather challenging case study for QM-cluster models because convergence in energetics requires models with >350 atoms. "Maximal" QM-cluster models built with either qualitative contact count ranking or quantitative interaction energies from functional group symmetry adapted perturbation theory provide acceptable results. Hence, important residue fragments that contribute to the energetics of the methyl-transfer reaction in GNMT are correctly identified in the RIN. Observations from this work suggest new directions to better establish an effective approach for constructing atomic-level enzyme models.

Neutral gas pressure dependence of ion-ion mutual neutralization rate constants using Landau-Zener theory coupled with trajectory simulations.

In this computational study, we describe a self-consistent trajectory simulation approach to capture the effect of neutral gas pressure on ion-ion mutual neutralization (MN) reactions. The electron transfer probability estimated using Landau-Zener (LZ) transition state theory is incorporated into classical trajectory simulations to elicit predictions of MN cross sections in vacuum and rate constants at finite neutral gas pressures. Electronic structure calculations with multireference configuration interaction and large correlation consistent basis sets are used to derive inputs to the LZ theory. The key advance of our trajectory simulation approach is the inclusion of the effect of ion-neutral interactions on MN using a Langevin representation of the effect of background gas on ion transport. For H+ - H- and Li+ - H(D)-, our approach quantitatively agrees with measured speed-dependent cross sections for up to ∼105 m/s. For the ion pair Ne+ - Cl-, our predictions of the MN rate constant at ∼1 Torr are a factor of ∼2 to 3 higher than the experimentally measured value. Similarly, for Xe+ - F- in the pressure range of ∼20 000-80 000 Pa, our predictions of the MN rate constant are ∼20% lower but are in excellent qualitative agreement with experimental data. The paradigm of using trajectory simulations to self-consistently capture the effect of gas pressure on MN reactions advanced here provides avenues for the inclusion of additional nonclassical effects in future work.

Evaluating the active site-substrate interplay between x-ray crystal structure and molecular dynamics in chorismate mutase.

Designing realistic quantum mechanical (QM) models of enzymes is dependent on reliably discerning and modeling residues, solvents, and cofactors important in crafting the active site microenvironment. Interatomic van der Waals contacts have previously demonstrated usefulness toward designing QM-models, but their measured values (and subsequent residue importance rankings) are expected to be influenceable by subtle changes in protein structure. Using chorismate mutase as a case study, this work examines the differences in ligand-residue interatomic contacts between an x-ray crystal structure and structures from a molecular dynamics simulation. Select structures are further analyzed using symmetry adapted perturbation theory to compute ab initio ligand-residue interaction energies. The findings of this study show that ligand-residue interatomic contacts measured for an x-ray crystal structure are not predictive of active site contacts from a sampling of molecular dynamics frames. In addition, the variability in interatomic contacts among structures is not correlated with variability in interaction energies. However, the results spotlight using interaction energies to characterize and rank residue importance in future computational enzymology workflows.

Nitrile regio-synthesis by Ni centers on a siliceous surface: implications in prebiotic chemistry.

By means of quantum chemistry (PBE0/def2-TZVPP; DLPNO-CCSD(T)/cc-pVTZ) and small, but reliable models of Polyhedral Oligomeric Silsesquioxanes (POSS), an array of astrochemically-relevant catalysis products, related to prebiotic and origin of life chemistry, has been theoretically explored. In this work, the heterogeneous phase hydrocyanation reaction of an unsaturated CC bond (propene) catalyzed by a Ni center complexed to a silica surface is analyzed. Of the two possible regioisomers, the branched iso-propyl-cyanide is thermodynamically and kinetically preferred over the linear n-propyl-cyanide (T = 200 K). The formation of nitriles based on a regioselective process has profound implications on prebiotic and origin of life chemistry, as well as deep connections to terrestrial surface chemistry and geochemistry.

Theoretical Rovibrational Spectroscopy of Magnesium Tricarbide-Multireference Character Thwarts a Full Analysis of All Isomers.

Magnesium tricarbide isomers are studied herein with coupled cluster theory and multireference configuration interaction to support their possible detection in astrochemical environments such as the circumstellar envelope surrounding the star IRC +10216 or in terrestrial laboratories. Magnesium-bearing species may abound in the interstellar medium (ISM), but only eight (MgNC, MgCN, HMgNC, MgC2H, MgC3N, MgC4H, MgC5N, and MgC6H) have been directly identified thus far. Several possible isomers for the related MgC3 system are explored in their singlet and triplet spin multiplicities. Overall, this work offers quantum chemical insight of rovibrational spectroscopic data for MgC3 using quartic force fields (QFFs) based on the CCSD(T) and CCSD(T)-F12 levels of theory at the complete basis set (CBS) limit. Additional corrections with small basis set CCSDT(Q) and scalar relativistic effects are also included in the analysis. Salient multireference character is found in the singlet diamond electronic state, which makes a definitive assignment of the ground state challenging. Nevertheless, coupled cluster-based composite energies and multireference configuration interaction both predict that the 1A1 diamond isomer is 1.6-2.2 kcal mol-1 lower in energy than the 3A1 diamond isomer. Furthermore, highly accurate binding energies of various isomers MgC3 are provided for comparison to photodetachment experiments. Dipole moments along with harmonic infrared intensities will guide efforts for astronomical and spectroscopic characterization.

Cheminformatic quantum mechanical enzyme model design: A catechol-O-methyltransferase case study.

To accurately simulate the inner workings of an enzyme active site with quantum mechanics (QM), not only must the reactive species be included in the model but also important surrounding residues, solvent, or coenzymes involved in crafting the microenvironment. Our lab has been developing the Residue Interaction Network Residue Selector (RINRUS) toolkit to utilize interatomic contact network information for automated, rational residue selection and QM-cluster model generation. Starting from an x-ray crystal structure of catechol-O-methyltransferase, RINRUS was used to construct a series of QM-cluster models. The reactant, product, and transition state of the methyl transfer reaction were computed for a total of 550 models, and the resulting free energies of activation and reaction were used to evaluate model convergence. RINRUS-designed models with only 200-300 atoms are shown to converge. RINRUS will serve as a cornerstone for improved and automated cheminformatics-based enzyme model design.

QM-Cluster Model Study of the Guaiacol Hydrogen Atom Transfer and Oxygen Rebound with Cytochrome P450 Enzyme GcoA.

The key step of the O-demethylation of guaiacol by GcoA of the cytochrome P450-reductase pair was studied with DFT using two 10-residue and three 15-residue QM-cluster models. For each model, two reaction pathways were examined, beginning with a different guaiacol orientation. Based on this study, His354, Phe349, Glu249, and Pro250 residues were found to be important for keeping the heme in a planar geometry throughout the reaction. Val241 and Gly245 residues were needed in the QM-cluster models to provide the hydrophobic pocket for an appropriate guaiacol pose in the reaction. The aromatic triad Phe75, Phe169, and Phe395 may be necessary to facilitate guaiacol migrating into the enzyme active site, but it does not qualitatively affect kinetics and thermodynamics of the proposed mechanism. All QM-cluster models created by RINRUS agree very well with previous experimental work. This study provides details for better understanding enzymatic O-demethylation of lignins to form catechol derivatives by GcoA.

Rovibrational Quantum Chemical Treatment of Inorganic and Organometallic Astrochemicals.

ConspectusOur two groups have both independently and collaboratively been pushing quantum-chemical techniques to produce highly accurate predictions of anharmonic vibrational frequencies and spectroscopic constants for molecules containing atoms outside of the typical upper p block. Methodologies employ composite approaches, relying on various levels of coupled cluster theory-most often at the singles, doubles, and perturbative triples level-and quartic force field constructions of the potential portion of the intramolecular Watson Hamiltonian. Such methods are known to perform well for organic species, and we have extended this to molecules containing atoms outside of this realm.One notable atom that has received much attention in this application is magnesium. Mg is the second-most-abundant element in the Earth's mantle, and while molecules containing this element are among the confirmed astrochemicals, its further atomic abundance in the galaxy implies that many more molecules (both purely inorganic and organometallic) containing element 12 exist in astrophysical regions in chemical sizes between those of atoms and dust-sized nanocrystals. Our approach discussed herein is producing quality benchmarks and predicting novel data for magnesium-bearing molecules.The story is similar for Al and Si, which are also notably abundant in both rocky bodies and the universe at large. While Na, Sc, and Cu may not be as abundant as Mg, Al, and Si, molecules containing Na and transition metals have also previously been reported to be detected beyond the Earth. Consequently, the need to produce spectral reference data for molecules containing such atoms is growing. While several experimental groups (including, notably, the groups in Arizona, Boston, and France/Spain) have clearly led the way in detection of inorganic/organometallic molecules in space, computational support and even rational design can provide novel avenues for the detection of molecules containing atoms not typically studied in most laboratories. The application of quantum chemistry to other elements beyond carbon and its cronies at the top right of the periodic table promises a better understanding of the observable universe. It will also provide novel and fundamental chemical insights pushing the "central science" into new molecular territory.

CO2 Capture by 2-(Methylamino)pyridine Ligated Aluminum Alkyl Complexes.

A set of novel, easily synthesized aluminum complexes, Al[κ2-N,N-2-(methylamino)pyridine]2R (R = Et, iBu) are reported. When subjected to 1 atm of CO2 pressure, each hemilabile pyridine arm dissociates and facilitates cooperative activation of the CO2 substrate reminiscent of a Frustrated Lewis Pair. This reaction has limited precedent for Al/N based Lewis Pair systems, and this is the first system readily shown to sequester multiple equivalents of CO2 per aluminum center. The ethyl variant then reacts further, inserting a third equivalent of CO2 into the aluminum alkyl to generate an aluminum carboxylate. Examples of this type of reactivity are rare under thermal conditions. A joint experimental/computational study supports the proposed reaction mechanism.

Systematic evaluation of the electronic effect of aluminum-containing ligands in iridium-aluminum and rhodium-aluminum bimetallic complexes.

Pyridinemethanolate and oxyquinoline derivatives of previously reported late transition metal-aluminum heterobimetallic complexes containing iridium and rhodium have been synthesized and characterized. A combination of experimental and computational data permits a direct comparison of the electronic effects of each novel aluminum-containing ligand in our library on the late transition metal centers. Alongside electronic data of previously reported oxypyridine bridged systems, we conclude that the addition of a dialkylaluminum(X) (X = anion) fragment does not significantly perturb the electron donor ability of the bridging ligand. Anions bound to the aluminum are also shown to behave similarly. The overall library, thus, suggests that the best predictor of the electron donor ability of an alkylaluminum-containing ligand to a transition metal is the donor power of the bridging ligand.

Acylation and deacylation mechanism and kinetics of penicillin G reaction with Streptomyces R61 DD-peptidase.

Two quantum mechanical (QM)-cluster models are built for studying the acylation and deacylation mechanism and kinetics of Streptomyces R61 DD-peptidase with the penicillin G at atomic level detail. DD-peptidases are bacterial enzymes involved in the cross-linking of peptidoglycan to form the cell wall, necessary for bacterial survival. The cross-linking can be inhibited by antibiotic beta-lactam derivatives through acylation, preventing the acyl-enzyme complex from undergoing further deacylation. The deacylation step was predicted to be rate-limiting. Transition state and intermediate structures are found using density functional theory in this study, and thermodynamic and kinetic properties of the proposed mechanism are evaluated. The acyl-enzyme complex is found lying in a deep thermodynamic sink, and deacylation is indeed the severely rate-limiting step, leading to suicide inhibition of the peptidoglycan cross-linking. The usage of QM-cluster models is a promising technique to understand, improve, and design antibiotics to disrupt function of the Streptomyces R61 DD-peptidase.

Complex Organic Matter Synthesis on Siloxyl Radicals in the Presence of CO.

Heterogeneous phase astrochemistry plays an important role in the synthesis of complex organic matter (COM) as found on comets and rocky body surfaces like asteroids, planetoids, moons and planets. The proposed catalytic model is based on two assumptions: (a) siliceous rocks in both crystalline or amorphous states show surface-exposed defective centers such as siloxyl (Si-O•) radicals; (b) the second phase is represented by gas phase CO molecules, an abundant C1 building block found in space. By means of quantum chemistry; (DFT, PW6B95/def2-TZVPP); the surface of a siliceous rock in presence of CO is modeled by a simple POSS (polyhedral silsesquioxane) where a siloxyl (Si-O•) radical is present. Four CO molecules have been consecutively added to the Si-O• radical and to the nascent polymeric CO (pCO) chain. The first CO insertion shows no activation free energy with ΔG200K = -21.7 kcal/mol forming the SiO-CO• radical. The second and third CO insertions show Δ G 200 K ‡ ≤ 10.5 kcal/mol. Ring closure of the SiO-CO-CO• (oxalic anhydride) moiety as well as of the SiO-CO-CO-CO• system (di-cheto form of oxetane) are thermodynamically disfavored. The last CO insertion shows no free energy of activation resulting in the stable five member pCO ring, precursor to 1,4-epoxy-1,2,3-butanone. Hydrogenation reactions of the pCO have been considered on the SiO oxygen or on the carbons and oxygens of the pCO chains. The formation of the reactive aldehyde SiO-CHO on the siliceous surface is possible. In principle, the complete hydrogenation of the (CO)1-4 series results in the formation of methanol and polyols. Furthermore, all the SiO-pCO intermediates and the lactone 1,4-epoxy-1,2,3-butanone product in its radical form can be important building blocks in further polymerization reactions and/or open ring reactions with H (aldehydes, polyols) or CN (chetonitriles), resulting in highly reactive multi-functional compounds contributing to COM synthesis.

Quantifying Inter-Residue Contacts through Interaction Energies.

The validity and accuracy of protein modeling is dependent on constructing models that account for the inter-residue interactions crucial for protein structure and function. Residue interaction networks derived from interatomic van der Waals contacts have previously demonstrated usefulness toward designing protein models, but there has not yet been evidence of a connection between network-predicted interaction strength and quantitative interaction energies. This work evaluates the intraprotein contact networks of five proteins against ab initio interaction energies computed using symmetry-adapted perturbation theory. To more appropriately capture the local chemistry of the protein, we deviate from traditional protein network analysis to redefine the interacting nodes in terms of main chain and side chain functional groups rather than complete amino acids. While there is no simple correspondence between the features of the contact network and actual interaction strength, random forest models constructed from minimal structural, network, and chemical descriptors are capable of accurately predicting interaction energy. The results of this work serve as a foundation for the development and improvement of functional group-based contact networks.

Hydrogen Activation and Hydrogenolysis Facilitated By Late-Transition-Metal-Aluminum Heterobimetallic Complexes.

Previously reported heterobimetallic rhodium-aluminum and iridium-aluminum alkyl complexes are shown to activate hydrogen, generating the corresponding alkane. Kinetic data indicate a mechanistic difference between the iridium- and rhodium-based systems. In both cases the transition metal is an active participant in the release of alkane from the aluminum center. For iridium-aluminum species, experimental mechanistic data suggest that multiple pathways occur concomitantly with each other: one being the oxidative addition of hydrogen followed by proton transfer resulting in alkane generation. Computational data indicate a reasonable barrier to formation of an iridium dihydride intermediate observed experimentally. In the case of the rhodium-aluminum species, hydrides are not observed spectroscopically, though a reasonable barrier to formation of this thermodynamically unstable species has been calculated. Alternative mechanistic possibilities are discussed and explored computationally. Cooperative hydrogenolysis mechanisms are computed to be energetically unfeasible for both metal centers.

Photodynamics of [FeFe]-Hydrogenase Model Compounds with Bidentate Heterocyclic Ligands.

Two asymmetrically structured model compounds for the hydrogen-generating [Fe-Fe]-hydrogenase active site were investigated to determine the ultrafast photodynamics, structural intermediates, and photoproducts compared to more common symmetric di-iron species. The bidentate-ligand-containing compounds studied were Fe2(µ-S2C3H6)(CO)4(bipy), 1, and Fe2(µ-S2C3H6)(CO)4(phen), 2, in dilute room temperature acetonitrile solution and low-temperature 2Me-THF matrix isolation using static FTIR difference and time-resolved infrared spectroscopic methods (TRIR). Ultraviolet-visible spectra were also compared to time-dependent density functional theory (TD-DFT) to ascertain the orbital origins of long wavelength electronic absorption features. The spectroscopic evidence supports the conclusions that only a propyl-bridge flip occurs in low-temperature matrix, while early time CO ejection leads to the formation of solvated isomeric species on the 25 ps time scale in room temperature solution.

Theoretical study of the low-lying electronic states of iron hydride cation.

Both FeH and FeH+ are predicted to be abundant in cool stellar atmospheres and proposed to be molecular components of the gas phase interstellar medium (ISM). However, experimental and simulated data for both species are lacking, which have hindered astronomical detection. There are no published laboratory data for the spectroscopy of FeH+ in any frequency regime. It is also not established if FeH+ possesses salient multireference character, which would pose significant challenges for ab initio modeling of geometric and spectroscopic properties. With a set of high-level coupled cluster and multireference configuration interaction computations, a study of the electronic structure of the ground state and seven excited states of FeH+ was carried out. An X5Δi electronic ground state of FeH+ is found, in agreement with previous theoretical studies. Including corrections for spin-orbit coupling and anharmonic vibrational effects, the Ω = 3, ν = 0 spin ladder of the A5Πi electronic state lies 872 cm-1 higher in energy than the Ω = 4, ν = 0 spin ladder of the ground state. Combined with previous work in our laboratory, the ionization energy of FeH is computed to be 7.4851 eV. With modern multireference configuration interaction and coupled cluster methods, spectroscopic constants (re, Be, ωe, ωexe, αe, and D¯e) for several bound excited states (A5Πi, B 5Σi +, a 3Σr -, b3Φi, c3Πi, d3Δr, and 7Σ+) were characterized. This study will lead efforts to identify FeH+ in the ISM and help solve important remaining questions in quantifying metal-hydride bonding.

On the formation of phosphorous polycyclic aromatics hydrocarbons (PAPHs) in astrophysical environments.

The formation of phosphorous-containing polycyclic aromatic hydrocarbons (PAPHs) in astrophysical contexts is proposed and analyzed by means of computational methods [B3LYP-D3BJ/ma-def2-TZVPP, MP2-F12, CCSD-F12b and CCSD(T)-F12b levels of theory]. A "bottom-up" approach based on a radical-neutral reaction scheme between acetylene (C2H2) and the CP radical was used investigating: (a) the synthesis of the first PAPH (C5H5P) "phosphinine"; (b) PAPH growth by addition of C2H2 to the C5H4P radical; (c) PAPH synthesis by addition reactions of one CP radical and nC2H2 to a neutral PAH. Results show: (I) the formation of the phosphinine radical has a strong thermodynamic tendency (-133.3 kcal mol-1) and kinetic barriers ≤5.4 kcal mol-1; (II) PAPH growth by nC2H2 addition on the radical phosphinine easily and exothermically produces radicals (1a- or 1-phospha-naphtalenes with kinetic barriers ≤7.1 kcal mol-1 and reaction free energies ≤-102.5 kcal mol-1); (III) the addition of a single CP + nC2H2 to a neutral benzene generates a complex chemistry where the main product is 2-phospha-naphtalene; (IV) because of the CP radical character, its barrierless addition to a PAH produces a resonant stabilized PAPH, becoming excellent candidates for addition reactions with neutral or radical hydrocarbons and PAHs; (V) the same energy trend between all four levels of theory continues a well-calibrated computational protocol to analyze complex organic reactions with astrochemical interest using electronic structure theory.

Propylene Oxide Formation on a Silica Surface with Peroxo Defects: Implications in Astrochemistry.

The formation of the chiral molecule propylene oxide (CH3CHCH2O) recently detected in the interstellar medium (ISM) is proposed to take place on an amorphous silicate grain surface where peroxo defects are present. A computational analysis conducted at the DFT and MP2-F12 levels of theory on a neat amorphous silica model supports such a hypothesis resulting in (a) strong thermodynamic driving forces and low activation energies allowing the synthesis of CH3CHCH2O at low temperatures, (b) chemical defects on silica surfaces promoting heterogeneous catalysis of the increasing molecular complexity found in interstellar and circumstellar medium, and (c) chemical defects that have implications on understanding how processing phases modify the nature of the reactive groups on a silica surface affecting the surface catalytic activity.