Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance.

Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.

Equilibrium Structures of the Phosphorus Trihalides PF3 and PCl3, and the Phosphoranes PH3F2, PF5, PCl3F2, and PCl5.

Among the title species, a reliable and accurate equilibrium geometry ( re structure) is available only for PF3, which has been determined experimentally more than 20 years ago. Here, we report accurate re structures for all title molecules, which were obtained using a composite computational approach based on explicitly correlated coupled-cluster theory (CCSD(T)-F12b) in conjunction with a large correlation-consistent basis set (cc-pCVQZ-F12) to take core-valence electron correlation into account. Additional terms were included to correct for the effects of iterative triple excitations (CCSDT), noniterative quadruple excitations (CCSDT(Q)), and scalar relativistic contributions (DKH2-CCSD(T)). The performance of this computational procedure was established through test calculations on selected small molecules (PH, PF, PCl, PH2, PF2, and PH3). For PF3, PCl3, PH3F2, and PF5 sufficiently accurate experimental ground-state rotational constants from the literature were used to determine semiexperimental re structures, which were found to be in excellent agreement with the corresponding best estimates from the current composite approach. The recommended equilibrium structural parameters are for PCl3, re(PCl) = 203.94 pm and θe(ClPCl) = 100.18°; for PH3F2, re(PHeq) = 138.38 pm and re(PFax) = 164.15 pm; for PF5, re(PFeq) = 153.10 pm and re(PFax) = 157.14 pm; for PCl3F2, re(PCleq) = 200.21 pm and re(PFax) = 159.37 pm; and for PCl5, re(PCleq) = 201.29 pm and re(PClax) = 211.83 pm. The associated uncertainties are estimated to be ±0.10 pm and ±0.10°, respectively.

QM/MM study of the taxadiene synthase mechanism.

Combined quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the reaction mechanism of taxadiene synthase (TXS). TXS catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to taxadiene (T) and four minor cyclic products. All these products originate from the deprotonation of carbocation intermediates. The reaction profiles for the conversion of GGPP to T as well as to minor products were calculated for different configurations of relevant TXS carbocation complexes. The QM region was treated at the M06-2X/TZVP level, while the CHARMM27 force field was used to describe the MM region. The QM/MM calculations suggest a reaction pathway for the conversion of GGPP to T, which slightly differs from previous proposals regarding the number of reaction steps and the conformation of the carbocations. The QM/MM results also indicate that the formation of minor products via water-assisted deprotonation of the carbocations is highly exothermic, by about -7 to -23 kcal/mol. Curiously, however, the computed barriers and reaction energies indicate that the formation of some of the minor products is more facile than the formation of T. Thus, the present QM/MM calculations provide detailed insights into possible reaction pathways and into the origin of the promiscuity of TXS, but they do not reproduce the product distribution observed experimentally. © 2019 Wiley Periodicals, Inc.

Semiempirical Quantum-Chemical Methods with Orthogonalization and Dispersion Corrections.

We present two new semiempirical quantum-chemical methods with orthogonalization and dispersion corrections: ODM2 and ODM3 (ODM x). They employ the same electronic structure model as the OM2 and OM3 (OM x) methods, respectively. In addition, they include Grimme's dispersion correction D3 with Becke-Johnson damping and three-body corrections E ABC for Axilrod-Teller-Muto dispersion interactions as integral parts. Heats of formation are determined by adding explicitly computed zero-point vibrational energy and thermal corrections, in contrast to standard MNDO-type and OM x methods. We report ODM x parameters for hydrogen, carbon, nitrogen, oxygen, and fluorine that are optimized with regard to a wide range of carefully chosen state-of-the-art reference data. Extensive benchmarks show that the ODM x methods generally perform better than the available MNDO-type and OM x methods for ground-state and excited-state properties, while they describe noncovalent interactions with similar accuracy as OM x methods with a posteriori dispersion corrections.

The rotation-vibration spectrum of methyl fluoride from first principles.

Accurate ab initio calculations on the rotation-vibration spectrum of methyl fluoride (CH3F) are reported. A new nine-dimensional potential energy surface (PES) and dipole moment surface (DMS) have been generated using high-level electronic structure methods. Notably, the PES was constructed from explicitly correlated coupled cluster calculations with extrapolation to the complete basis set limit and considered additional energy corrections to account for core-valence electron correlation, higher-order coupled cluster terms beyond perturbative triples, scalar relativistic effects, and the diagonal Born-Oppenheimer correction. The PES and DMS are evaluated through robust variational nuclear motion computations of pure rotational and vibrational energy levels, the equilibrium geometry of CH3F, vibrational transition moments, absolute line intensities of the ν6 band, and the rotation-vibration spectrum up to J = 40. The computed results show excellent agreement with a range of experimental sources, in particular the six fundamentals are reproduced with a root-mean-square error of 0.69 cm-1. This work represents the most accurate theoretical treatment of the rovibrational spectrum of CH3F to date.

Big data analysis of ab Initio molecular integrals in the neglect of diatomic differential overlap approximation.

Most modern semiempirical quantum-chemical (SQC) methods are based on the neglect of diatomic differential overlap (NDDO) approximation to ab initio molecular integrals. Here, we check the validity of this approximation by computing all relevant integrals for 32 typical organic molecules using Gaussian-type orbitals and various basis sets (from valence-only minimal to all-electron triple-ζ basis sets) covering in total more than 15.6 million one-electron (1-e) and 10.3 billion two-electron (2-e) integrals. The integrals are calculated in the nonorthogonal atomic basis and then transformed by symmetric orthogonalization to the Löwdin basis. In the case of the 1-e integrals, we find strong orthogonalization effects that need to be included in SQC models, for example, by strategies such as those adopted in the available OMx methods. For the valence-only minimal basis, we confirm that the 2-e Coulomb integrals in the Löwdin basis are quantitatively close to their counterparts in the atomic basis and that the 2-e exchange integrals can be safely neglected in line with the NDDO approximation. For larger all-electron basis sets, there are strong multishell orthogonalization effects that lead to more irregular patterns in the transformed 2-e integrals and thus cast doubt on the validity of the NDDO approximation for extended basis sets. Focusing on the valence-only minimal basis, we find that some of the NDDO-neglected integrals are reduced but remain sizable after the transformation to the Löwdin basis; this is true for the two-center 2-e hybrid integrals, the three-center 1-e nuclear attraction integrals, and the corresponding three-center 2-e hybrid integrals. We consider a scheme with a valence-only minimal basis that includes such terms as a possible strategy to go beyond the NDDO integral approximation in attempts to improve SQC methods. © 2018 Wiley Periodicals, Inc.

On the convergence of multi-scale free energy simulations.

In this work we employ simple model systems to evaluate the relative performance of two of the most important free energy methods: The Zwanzig equation (also known as "Free energy perturbation") and Bennett's acceptance ratio method (BAR). Although our examples should be transferable to other kinds of free energy simulations, we focus on applications of multi-scale free energy simulations. Such calculations are especially complex, since they connect two different levels of theory with very different requirements in terms of speed, accuracy, sampling and parallelizability. We try to reconcile all those different factors by developing some simple criteria to guide the early stages of the development of a free energy protocol. This is accomplished by quantifying how many λ intermediate steps and how many potential energy evaluations are necessary in order to reach a certain level of convergence.

Mechanism of the Visible-Light-Mediated Copper-Catalyzed Coupling Reaction of Phenols and Alkynes.

A recent experimental study reported a visible-light-mediated aerobic oxidative coupling reaction of phenol with alkynes that produces hydroxyl-functionalized aryl ketones using inexpensive CuCl as catalyst under mild conditions. Here we apply the complete active space self-consistent field (CASSCF) method and multistate second-order perturbation (MS-CASPT2) theory in combination with density functional theory (DFT) to systematically explore the entire photocatalytic reaction between phenol and phenylacetylene in acetonitrile solution in the presence of molecular oxygen and CuCl. Our main findings are as follows: (1) The visible-light-driven conversion of phenylacetylene to PhCCCu(I) occurs thermally because of efficient excited-state deactivation to the S0 state. (2) The single electron transfer from PhCCCu(I) to molecular oxygen that leads to the PhCCCu(II) cation takes place in the T1 state after an efficient S1 → T1 intersystem crossing. (3) During the initial oxidation of phenol, molecular oxygen prefers to attack the para position of the phenol radical intermediate to produce 1,4-benzoquinone, which further reacts with PhCCCu(II) to generate para-hydroxyl-substituted aryl ketones; this is the origin of the experimentally observed regioselectivity. (4) The C≡C bond of the phenylacetylene moiety is not activated by the triplet-state single electron transfer from PhCCCu(I) to molecular oxygen but is cleaved at a later stage, in the [2+2] cycloaddition between PhCCCu(II) and 1,4-benzoquinone. (5) The substrate phenol plays an active role in several hydrogen transfer and decarboxylation reactions; the barriers to these phenol-assisted reactions are lower than those for the corresponding direct or water-assisted reactions, which explains the experimental finding that adding water does not enhance the photocatalytic reaction yield. In summary, while supporting the general features of the experimentally proposed mechanism, our computational study provides detailed mechanistic insights that should be useful for understanding and further improving visible-light-induced copper-catalyzed coupling reactions.

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes.

Maintaining a proper balance between specific intermolecular interactions and non-specific solvent interactions is of critical importance in molecular simulations, especially when predicting binding affinities or reaction rates in the condensed phase. The most rigorous metric for characterizing solvent affinity are solvation free energies, which correspond to a transfer from the gas phase into solution. Due to the drastic change of the electrostatic environment during this process, it is also a stringent test of polarization response in the model. Here, we employ both the CHARMM fixed charge and polarizable force fields to predict hydration free energies of twelve simple solutes. The resulting classical ensembles are then reweighted to obtain QM/MM hydration free energies using a variety of QM methods, including MP2, Hartree⁻Fock, density functional methods (BLYP, B3LYP, M06-2X) and semi-empirical methods (OM2 and AM1 ). Our simulations test the compatibility of quantum-mechanical methods with molecular-mechanical water models and solute Lennard⁻Jones parameters. In all cases, the resulting QM/MM hydration free energies were inferior to purely classical results, with the QM/MM Drude force field predictions being only marginally better than the QM/MM fixed charge results. In addition, the QM/MM results for different quantum methods are highly divergent, with almost inverted trends for polarizable and fixed charge water models. While this does not necessarily imply deficiencies in the QM models themselves, it underscores the need to develop consistent and balanced QM/MM interactions. Both the QM and the MM component of a QM/MM simulation have to match, in order to avoid artifacts due to biased solute⁻solvent interactions. Finally, we discuss strategies to improve the convergence and efficiency of multi-scale free energy simulations by automatically adapting the molecular-mechanics force field to the target quantum method.

Nonadiabatic Excited-State Dynamics with Machine Learning.

We show that machine learning (ML) can be used to accurately reproduce nonadiabatic excited-state dynamics with decoherence-corrected fewest switches surface hopping in a 1-D model system. We propose to use ML to significantly reduce the simulation time of realistic, high-dimensional systems with good reproduction of observables obtained from reference simulations. Our approach is based on creating approximate ML potentials for each adiabatic state using a small number of training points. We investigate the feasibility of this approach by using adiabatic spin-boson Hamiltonian models of various dimensions as reference methods.

Analytic gradient and derivative couplings for the spin-flip extended configuration interaction singles method: Theory, implementation, and application to proton transfer.

We present the formalism of analytic gradients and derivative couplings for the spin-flip extended configuration interaction with single excitations (SF-XCIS) method. We report an efficient implementation of the SF-XCIS method in the framework of semiempirical quantum chemistry that allows fast excited-state calculations for large systems. The performance of the SF-XCIS method in combination with semiempirical orthogonalization-corrected models (OMx) is statistically evaluated for vertical singlet excitation energies. The SF-XCIS method treats the ground state and excited states in a fully balanced manner and properly describes conical intersections involving the ground state. It can thus be used in fewest switches surface hopping (FSSH) simulations of nonadiabatic dynamics processes. This is demonstrated in an OM2/SF-XCIS FSSH pilot study of excited-state proton transfer in 7-(2-pyridyl)indole.

Toward Accurate QM/MM Reaction Barriers with Large QM Regions Using Domain Based Pair Natural Orbital Coupled Cluster Theory.

The hydroxylation reaction catalyzed by p-hydroxybenzoate hydroxylase and the Baeyer-Villiger reaction catalyzed by cyclohexanone monooxygenase are investigated by means of quantum mechanical/molecular mechanical (QM/MM) calculations at different levels of QM theory. The geometries of the stationary points along the reaction profile are obtained from QM/MM geometry optimizations, in which the QM region is treated by density functional theory (DFT). Relative energies are determined from single-point QM/MM calculations using the domain-based local pair natural orbital coupled cluster DLPNO-CCSD(T) method as QM component. The results are compared with single-point DFT/MM energies obtained using popular density functionals and with available experimental and computational data. It is found that the choice of the QM method strongly affects the computed energy profiles for these reactions. Different density functionals provide qualitatively different energy barriers (variations of the order of 10 kcal/mol in both reactions), thus limiting the confidence in DFT/MM computational predictions of energy profiles. On the other hand, the use of the DLPNO-CCSD(T) method in conjunction with large QM regions and basis sets makes it possible to achieve high accuracy. A critical discussion of all the technical aspects of the calculations is given with the aim of aiding computational chemists in the application of the DLPNO-CCSD(T) methodology in QM/MM calculations.

1-Butanol as a Solvent for Efficient Extraction of Polar Compounds from Aqueous Medium: Theoretical and Practical Aspects.

The extraction of polar molecules from aqueous solution is a challenging task in organic synthesis. 1-Butanol has been used sporadically as an eluent for polar molecules, but it is unclear which molecular features drive its efficiency. Here, we employ free energy simulations to study the partitioning of 15 solutes between water and 1-butanol. The simulations demonstrate that the high affinity of polar molecules to the wet 1-butanol phase is associated with its nanostructure. Small inverse micelles of water are able to accommodate polar solutes and locally mimic an aqueous environment. We verify the simulations based on partition coefficients between water and 1-octanol, and include a blind prediction of the water/1-butanol partition coefficient of cyclohexane-1,2-diol. The calculations are in excellent agreement with experiment, reaching root-mean-square deviations below 0.7 kcal/mol. Actual extractions of cyclohexane-1,2-diol from buffer solutions that mimic cell lysates and suspensions in biocatalytic reactions further exemplify our findings. The yields highlight that extractions with 1-butanol can be significantly more efficient than the conventional protocol based on ethyl acetate.

An efficient implementation of semiempirical quantum-chemical orthogonalization-corrected methods for excited-state dynamics.

We present an efficient implementation of configuration interaction with single excitations (CIS) for semiempirical orthogonalization-corrected OMx methods and standard modified neglect of diatomic overlap (MNDO)-type methods for the computation of vertical excitation energies as well as analytical gradients and nonadiabatic couplings. This CIS implementation is combined with Tully's fewest switches algorithm to enable surface hopping simulations of excited-state nonadiabatic dynamics. We introduce an accurate and efficient expression for the semiempirical evaluation of nonadiabatic couplings, which offers a significant speedup for medium-size molecules and is suitable for use in long nonadiabatic dynamics runs. As a pilot application, the semiempirical CIS implementation is employed to investigate ultrafast energy transfer processes in a phenylene ethynylene dendrimer model.

Ultrafast action chemistry in slow motion: atomistic description of the excitation and fluorescence processes in an archetypal fluorescent protein.

We report quantum mechanical/molecular mechanical non-adiabatic molecular dynamics simulations on the electronically excited state of green fluorescent protein mutant S65T/H148D. We examine the driving force of the ultrafast (τ < 50 fs) excited-state proton transfer unleashed by absorption in the A band at 415 nm and propose an atomistic description of the two dynamical regimes experimentally observed [Stoner Ma et al., J. Am. Chem. Soc., 2008, 130, 1227]. These regimes are explained in terms of two sets of successive dynamical events: first the proton transfers quickly from the chromophore to the acceptor Asp148. Thereafter, on a slower time scale, there are geometrical changes in the cavity of the chromophore that involve the distance between the chromophore and Asp148, the planarity of the excited-state chromophore, and the distance between the chromophore and Tyr145. We find two different non-radiative relaxation channels that are operative for structures in the reactant region and that can explain the mismatch between the decay of the emission of A* and the rise of the emission of I*, as well as the temperature dependence of the non-radiative decay rate.

Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes.

The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a π-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic -OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem-hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions.

QM/MM Studies on Photoisomerization Dynamics of Azobenzene Chromophore Tethered to a DNA Duplex: Local Unpaired Nucleobase Plays a Crucial Role.

The photoresponsive azobenzene-tethered DNAs have received growing experimental attention because of their potential applications in biotechnology and nanotechnology; however, little is known about the initial photoisomerization of azobenzene in these systems. Herein we have employed quantum mechanics/molecular mechanics (QM/MM) methods to explore the photoisomerization dynamics of an azobenzene-tethered DNA duplex. We find that in the S1 state the trans-cis photoisomerization path is much steeper in DNA than in vacuo, which makes the photoisomerization much faster in the DNA environment. This acceleration is primarily caused by complex steric interactions between azobenzene and the nearby unpaired thymine nucleobase, which also change the photoisomerization mechanism of azobenzene in the DNA duplex.

Molecular dynamics study of taxadiene synthase catalysis.

Molecular dynamics (MD) simulations have been performed to study the dynamic behavior of noncovalent enzyme carbocation complexes involved in the cyclization of geranylgeranyl diphosphate to taxadiene catalyzed by taxadiene synthase (TXS). Taxadiene and the observed four side products originate from the deprotonation of carbocation intermediates. The MD simulations of the TXS carbocation complexes provide insights into potential deprotonation mechanisms of such carbocations. The MD results do not support a previous hypothesis that carbocation tumbling is a key factor in the deprotonation of the carbocations by pyrophosphate. Instead water bridges are identified which may allow the formation of side products via multiple proton transfer reactions. A novel reaction path for taxadiene formation is proposed on the basis of the simulations. © 2018 Wiley Periodicals, Inc.

Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels-Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels-Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels-Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels-Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geometries indicates that the enzyme may prearrange the substrate within the active site to accelerate the [4+2] cycloaddition and impede the [6+4] cycloaddition through interactions with active-site residues. Judging from partial charge analysis, we find that the hydrogen bond between the Thr196 residue of SpnF and the substrate C15 carbonyl group contributes to the enhancement of the rate of the Diels-Alder reaction. QM/MM simulations show that the substrate can easily adopt a reactive conformation in the active site of SpnF because interconversion between the C5-C6 s-trans and s-cis conformers is facile. Our QM/MM study suggests that the enzyme SpnF does behave as a Diels-Alderase.

Hot and Cold Charge-Transfer Mechanisms in Organic Photovoltaics: Insights into the Excited States of Donor/Acceptor Interfaces.

The evolution of the excited-state manifold in organic D/A aggregates (e.g., the prototypical P3HT/PCBM) is investigated through a bottom-up approach via first-principles calculations. We show how the excited-state energies, the charge transfer (CT) states, and the electron-hole density distributions are strongly influenced by the size, the orientation, and the position (i.e., on-top versus on-edge phases) of P3HT/PCBM domains. We discuss how the structural order influences the excited-state electronic structure, providing an atomistic interpretation of the photophysics of organic blends. We show how the simultaneous presence of on-top and on-edge phases does not alter the optical absorption spectrum of the blend but does affect the photophysics. Photovoltaic processes such as (i) the simultaneous charge generation obtained from hot and cold excitations, (ii) the instantaneous and delayed charge separation, and (iii) the pump-push-probe charge generation can be interpreted based on our study.