Systematic improvement of empirical energy functions in the era of machine learning.

The impact of targeted replacement of individual terms in empirical force fields is quantitatively assessed for pure water, dichloromethane (CH 2 Cl 2 ), and solvated K + and Cl - ions. For the electrostatic interactions, point charges (PCs) and machine learning (ML)-based minimally distributed charges (MDCM) fitted to the molecular electrostatic potential are evaluated together with electrostatics based on the Coulomb integral. The impact of explicitly including second-order terms is investigated by adding a fragment molecular orbital (FMO)-derived polarization energy to an existing force field, in this case CHARMM. It is demonstrated that anisotropic electrostatics reduce the RMSE for water (by 1.4 kcal/mol), CH 2 Cl 2 (by 0.8 kcal/mol) and for solvated Cl - clusters (by 0.4 kcal/mol). An additional polarization term can be neglected for CH 2 Cl 2 but further improves the models for pure water (by ∼ 1.0 kcal/mol) and hydrated Cl - (by 0.4 kcal/mol), and is key for solvated K + , reducing the RMSE by 2.3 kcal/mol. A 12-6 Lennard-Jones functional form performs satisfactorily with PC and MDCM electrostatics, but is not appropriate for descriptions that account for the electrostatic penetration energy. The importance of many-body contributions is assessed by comparing a strictly 2-body approach with self-consistent reference data. Two-body interactions suffice for CH 2 Cl 2 whereas water and solvated K + and Cl - ions require explicit many-body corrections. Finally, a many-body-corrected dimer potential energy surface exceeds the accuracy attained using a conventional empirical force field, potentially reaching that of an FMO calculation. The present work systematically quantifies which terms improve the performance of an existing force field and what reference data to use for parametrizing these terms in a tractable fashion for ML fitting of pure and heterogeneous systems.

Molecular Ansa-Basket: Synthesis of Inherently Chiral All-Carbon [12](1,6)Pyrenophane.

The synthesis of inherently chiral all-carbon C2-symmetric [12](1,6)pyrenophane 1 is reported. The cyclophane 1 was obtained via a ring-closing alkyne metathesis reaction using Mortreux's catalyst molybdenum hexacarbonyl and 2-fluorophenol as a phenol additive. The M and P enantiomers of the all-carbon pyrenophane 1 were demonstrated to be very stable in their enantiopure form even upon prolonged heating at 200 °C. [12](1,6)Pyrenophane-6-yne 1 was fully characterized by high-resolution mass spectrometry, nuclear magnetic resonance, UV-vis, and measured and calculated electronic circular dichroism spectroscopy.

Minimal distributed charges: Multipolar quality at the cost of point charge electrostatics.

Most empirical force fields use atom-centered point charges (PCs) to represent the electrostatic potential (ESP) around molecules. While such PC models are computationally efficient, they are unable to capture anisotropic electronic features, such as σ holes or lone pairs. These features are better described using atomic multipole (MTP) moments, which significantly improve the quality of the resulting ESP. However, the improvement comes at the expense of a considerably increased computational complexity and cost for calculating the interaction energies and forces. In the present work, a novel minimal distributed charge model (MDCM) based on off-centered point charges is presented and the quality of the resulting ESP is compared to the performance of MTPs and atom-centered PC models for several test molecules. All three models are fitted using the same algorithm based on differential evolution, which is available as a Fortran90 program from the authors upon request. We show that the MDCM is capable of approximating the reference ab initio ESP with an accuracy as good as, or better than, MTPs without the need for computationally expensive higher order multipoles. Further it is demonstrated that the MDCM is numerically stable in molecular dynamics simulations and is able to reproduce electrostatic interaction energies and thermodynamic quantities with the same accuracy as MTPs at reduced computational cost.

Quantum-chemistry based calibration of the alkali metal cation series (Li(+)-Cs(+)) for large-scale polarizable molecular mechanics/dynamics simulations.

The alkali metal cations in the series Li(+)-Cs(+) act as major partners in a diversity of biological processes and in bioinorganic chemistry. In this article, we present the results of their calibration in the context of the SIBFA polarizable molecular mechanics/dynamics procedure. It relies on quantum-chemistry (QC) energy-decomposition analyses of their monoligated complexes with representative O-, N-, S-, and Se- ligands, performed with the aug-cc-pVTZ(-f) basis set at the Hartree-Fock level. Close agreement with QC is obtained for each individual contribution, even though the calibration involves only a limited set of cation-specific parameters. This agreement is preserved in tests on polyligated complexes with four and six O- ligands, water and formamide, indicating the transferability of the procedure. Preliminary extensions to density functional theory calculations are reported.

A supervised fitting approach to force field parametrization with application to the SIBFA polarizable force field.

A supervised, semiautomated approach to force field parameter fitting is described and applied to the SIBFA polarizable force field. The I-NoLLS interactive, nonlinear least squares fitting program is used as an engine for parameter refinement while keeping parameter values within a physical range. Interactive fitting is shown to avoid many of the stability problems that frequently afflict highly correlated, nonlinear fitting problems occurring in force field parametrizations. The method is used to obtain parameters for the H2O, formamide, and imidazole molecular fragments and their complexes with the Mg(2+) cation. Reference data obtained from ab initio calculations using an auc-cc-pVTZ basis set exploit advances in modern computer hardware to provide a more accurate parametrization of SIBFA than has previously been available.

Back to the future: asymmetrical DπA 2,2'-bipyridine ligands for homoleptic copper(i)-based dyes in dye-sensitised solar cells.

Metal complexes used as sensitisers in dye-sensitised solar cells (DSCs) are conventionally constructed using a push-pull strategy with electron-releasing and electron-withdrawing (anchoring) ligands. In a new paradigm we have designed new DπA ligands incorporating diarylaminophenyl donor substituents and phosphonic acid anchoring groups. These new ligands function as organic dyes. For two separate classes of DπA ligands with 2,2'-bipyridine metal-binding domains, the DSCs containing the copper(i) complexes [Cu(DπA)2]+ perform better than the push-pull analogues [Cu(DD)(AA)]+. Furthermore, we have shown for the first time that the complexes [Cu(DπA)2]+ perform better than the organic DπA dye in DSCs. The synthetic studies and the device performances are rationalised with the aid of density functional theory (DFT) and time-dependent DFT (TD-DFT) studies.

Molecular Dynamics with Conformationally Dependent, Distributed Charges.

Accounting for geometry-induced changes in the electronic distribution in molecular simulation is important for capturing effects such as charge flow, charge anisotropy, and polarization. Multipolar force fields have demonstrated their ability to correctly represent chemically significant features such as anisotropy and sigma holes. It has also been shown that off-center point charges offer a compact alternative with similar accuracy. Here, it is demonstrated that allowing relocation of charges within a minimally distributed charge model (MDCM) with respect to their reference atoms is a viable route to capture changes in the molecular charge distribution depending on geometry, i.e., intramolecular polarization. The approach, referred to as "flexible MDCM" (fMDCM), is validated on a number of small molecules and provides accuracies in the electrostatic potential (ESP) of 0.5 kcal/mol on average compared with reference data from electronic structure calculations, whereas MDCM and point charges have root mean squared errors of a factor of 2 to 5 higher. In addition, MD simulations in the NVE ensemble using fMDCM for a box of flexible water molecules with periodic boundary conditions show a width of 0.1 kcal/mol for the fluctuation around the mean at 300 K on the 10 ns time scale. For water, the equilibrium valence angle in the gas phase is found to increase by 2° for simulations in the condensed phase which is consistent with experiment. The accuracy in capturing the geometry dependence of the ESP together with the long-time stability in energy conserving simulations makes fMDCM a promising tool to introduce advanced electrostatics into atomistic simulations.

The surprising effects of sulfur: achieving long excited-state lifetimes in heteroleptic copper(i) emitters.

A series of heteroleptic [Cu(N^N)(P^P)][PF6] complexes is reported in which N^N is a di(methylsulfanyl)-1,10-phenanthroline (2,9-, 3,8- or 4,7-(MeS)2phen) or di(methoxy)-1,10-phenanthroline (2,9-, 3,8- or 4,7-(MeO)2phen) and P^P is bis(2-(diphenylphosphano)phenyl)ether (POP) or 4,5-bis(diphenylphosphano)-9,9-dimethylxanthene (xantphos). The effects of the different substituents are investigated through structural, electrochemical and photophysical studies and by using DFT and TD-DFT calculations. Introducing methylsulfanyl groups in the 2,9-, 3,8- or 4,7-positions of the phen domain alters the composition of the frontier molecular orbitals of the [Cu(N^N)(P^P)]+ complexes significantly, so that ligand-centred (LC) transitions become photophysically relevant with respect to metal-to-ligand charge transfer (MLCT). Within this series, [Cu(2,9-(MeS)2phen)(POP)][PF6] exhibits the highest photoluminescence quantum yield of 15% and the longest excited-state lifetime of 8.3 µs in solution. In the solid state and in frozen matrices at 77 K, the electronic effects of the methylsulfanyl or methoxy substituents are highlighted, thus resulting in luminescence lifetimes of 2 to 4.2 ms at 77 K with predominantly LC character for both the 3,8- and 4,7-(MeS)2phen containing complexes. The results of the investigation give new guidelines on how to influence the luminescence properties in [Cu(N^N)(P^P)]+ complexes which will aid in the development of new sustainable and efficient copper(i) emitters.

Correction to "Mechanistic Insight into the Precursor Chemistry of ZrO2 and HfO2 Nanocrystals, toward Size-Tunable Syntheses".

[This corrects the article DOI: 10.1021/jacsau.1c00568.].

Mechanistic Insight into the Precursor Chemistry of ZrO2 and HfO2 Nanocrystals; towards Size-Tunable Syntheses.

One can nowadays readily generate monodisperse colloidal nanocrystals, but a retrosynthetic analysis is still not possible since the underlying chemistry is often poorly understood. Here, we provide insight into the reaction mechanism of colloidal zirconia and hafnia nanocrystals synthesized from metal chloride and metal isopropoxide. We identify the active precursor species in the reaction mixture through a combination of nuclear magnetic resonance spectroscopy (NMR), density functional theory (DFT) calculations, and pair distribution function (PDF) analysis. We gain insight into the interaction of the surfactant, tri-n-octylphosphine oxide (TOPO), and the different precursors. Interestingly, we identify a peculiar X-type ligand redistribution mechanism that can be steered by the relative amount of Lewis base (L-type). We further monitor how the reaction mixture decomposes using solution NMR and gas chromatography, and we find that ZrCl4 is formed as a by-product of the reaction, limiting the reaction yield. The reaction proceeds via two competing mechanisms: E1 elimination (dominating) and SN1 substitution (minor). Using this new mechanistic insight, we adapted the synthesis to optimize the yield and gain control over nanocrystal size. These insights will allow the rational design and synthesis of complex oxide nanocrystals.

Polarizable Multipolar Molecular Dynamics Using Distributed Point Charges.

Distributed point charge models (DCM) and their minimal variants (MDCM) have been integrated with tools widely used for condensed-phase simulations, including a virial-based barostat and a slow-growth algorithm for thermodynamic integration. Minimal DCM is further developed in a systematic fashion to reduce fitting errors in the electrostatic interaction energy, and a new fragment-based approach offers considerable speedup of the MDCM fitting process for larger molecules with increased numbers of off-centered charged sites. Finally, polarizable (M)DCM is also introduced in the present work. The developments are used in condensed-phase simulations of popular force fields with commonly applied simulation conditions. (M)DCM equivalents for a range of widely used water force fields and for fluorobenzene (PhF) are developed and applied along with the original models to evaluate the impact of reformulating the electrostatic term. Comparisons of the molecular electrostatic potential (MEP), electrostatic interaction energies, and bulk properties from molecular dynamics simulations for a range of models from simple TIPnP (n = 3-5) to the polarizable, multipolar iAMOEBA models for water and an existing quadrupolar model for PhF confirm that DCMs retain the accuracy of the original models, providing a homogeneous, efficient, and generic point charge alternative to a multipolar electrostatic model for force field development and multilevel simulations.

Stacked and H-Bonded Cytosine Dimers. Analysis of the Intermolecular Interaction Energies by Parallel Quantum Chemistry and Polarizable Molecular Mechanics.

Until now, atomistic simulations of DNA and RNA and their complexes have been executed using well calibrated but conceptually simple pair-additive empirical potentials (force fields). Although such simulations provided many valuable results, it is well established that simple force fields also introduce errors into the description, underlying the need for development of alternative anisotropic, polarizable molecular mechanics (APMM) potentials. One of the most abundant forces in all kinds of nucleic acids topologies is base stacking. Intra- and interstrand stacking is assumed to be the most essential factor affecting local conformational variations of B-DNA. However, stacking also contributes to formation of all kinds of noncanonical nucleic acids structures, such as quadruplexes or folded RNAs. The present study focuses on 14 stacked cytosine (Cyt) dimers and the doubly H-bonded dimer. We evaluate the extent to which an APMM procedure, SIBFA, could account quantitatively for the results of high-level quantum chemistry (QC) on the total interaction energies, and the individual energy contributions and their nonisotropic behaviors. Good agreements are found at both uncorrelated HF and correlated DFT and CCSD(T) levels. Resorting in SIBFA to distributed QC multipoles and to an explicit representation of the lone pairs is essential to respectively account for the anisotropies of the Coulomb and of the exchange-repulsion QC contributions.

A Novel, Computationally Efficient Multipolar Model Employing Distributed Charges for Molecular Dynamics Simulations.

A truncated multipole expansion can be re-expressed exactly using an appropriate arrangement of point charges. This means that groups of point charges that are shifted away from nuclear coordinates can be used to achieve accurate electrostatics for molecular systems. We introduce a multipolar electrostatic model formulated in this way for use in computationally efficient multipolar molecular dynamics simulations with well-defined forces and energy conservation in NVE (constant number-volume-energy) simulations. A framework is introduced to distribute torques arising from multipole moments throughout a molecule, and a refined fitting approach is suggested to obtain atomic multipole moments that are optimized for accuracy and numerical stability in a force field context. The formulation of the charge model is outlined as it has been implemented into CHARMM, with application to test systems involving H2O and chlorobenzene. As well as ease of implementation and computational efficiency, the approach can be used to provide snapshots for multipolar QM/MM calculations in QM/MM-MD studies and easily combined with a standard point-charge force field to allow mixed multipolar/point charge simulations of large systems.

Role of Cation Polarization in holo- and hemi-Directed [Pb(H2O)n](2+) Complexes and Development of a Pb(2+) Polarizable Force Field.

Reduced Variational Space (RVS) calculations are reported that afford insight into the energetic origins of the hemi- and holo-directing behavior of [Pb(H2O)n](2+) complexes. It is shown that the distribution of ligands around the Pb(2+) center arises from a delicate balance between the first-order Coulomb plus exchange-repulsion energy that favors holo-directionality, and the second-order charge transfer plus polarization term that favors hemi-directionality. It is additionally demonstrated that the pseudopotential/basis set combination used to study such complexes should be carefully selected, as artifacts can arise when using large-core pseudopotentials. Finally, based on these findings, we introduce a new SIBFA force field parametrization for Pb(2+). Results yield close agreement with ab initio complexation energies in a series of [Pb(H2O)n](2+) complexes and successfully encapsulate the hemi- and holo-directing properties. SIBFA thus appears to be the first classical force field to be able to model the holo-/hemi-directed transition within Pb complexes, avoiding the need for explicit wave function treatment and consequently providing the opportunity to deal with large leaded systems of biological interest.

In silico techniques for the identification of bioisosteric replacements for drug design.

This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compounds. The rapidly increasing number and diversity of methods has provided medicinal chemists with a powerful range of commercial and academic tools to aid in the optimization of lead compound activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calculated property space to cheminformatics analysis of pharmaceutical compound databases. We also discuss the incorporation, within these methods, of a whole spectrum of experimental and calculated data to describe fragment chemistry and compound activity. Despite the growing sophistication of available techniques, there remains much scope for further development and especially for deeper validation of the efficacy of different approaches in what seems set to remain an expanding field.

A refined model for prediction of hydrogen bond acidity and basicity parameters from quantum chemical molecular descriptors.

Abraham's H-bonding parameters alpha and beta have been described in terms of a minimal set of readily obtainable molecular descriptors. These parameters are basically equilibrium constants for complexation of acids with a reference base (alpha) or bases with a reference acid (beta) measured in a non-hydrogen bonding solvent such as tetrachloromethane. The models were developed using partial least squares with a diverse dataset recently compiled by Platts et al., encompassing a wide range of hydrogen bond acids and bases in order to give a robust model. Although less accurate than the model of Platts et al. the descriptors used in this work avoid expensive supermolecule calculations, and allow prediction of hydrogen bonding characteristics from the isolated molecular wave function. These descriptors can then be generated for a large number of compounds, making them ideal for storage in a quantum isostere database (QID), the construction of which we initiated. The QID is a web-based tool developed to predict bioisosteric replacements in lead optimisation projects. The current descriptors provide hydrogen bonding characteristics of molecules of interest.

Quantum Isostere Database: a web-based tool using quantum chemical topology to predict bioisosteric replacements for drug design.

This paper introduces the 'Quantum Isostere Database' (QID), a Web-based tool designed to find bioisosteric fragment replacements for lead optimization using stored ab initio data. A wide range of original geometric, electronic, and calculated physical properties are stored for each fragment. Physical descriptors with clear meaning are chosen, such as distribution of electrostatic potential energy values across a fragment surface and geometric parameters to describe fragment conformation and shape from ab initio structures. Further fundamental physical properties are linked to broader chemical characteristics relevant to biological activity, such as H-bond donor and acceptor strengths. Additional properties with less easily interpretable links to biological activity are also stored to allow future development of QSAR/QSPR models for quantities such as pK(a) and solubility. Conformational dependence of the ab initio descriptors is explicitly dealt with by storing properties for a variety of low-energy conformers of each fragment. Capping groups are used in ab initio calculations to represent different chemical environments, based on background research into transferability of electronic descriptors [J. Comput. Chem. 2009, 30, 1300-1318]. The resulting database has a Web interface that allows medicinal chemists to enter a query fragment, select important chemical features, and retrieve a list of suggested replacements with similar chemical characteristics. Examples of known bioisosteric replacements correctly identified by the QID tool are given.