Molecular-Level Examination of Amorphous Solid Dispersion Dissolution.

Amorphous solid dispersions (ASDs) are commonly used to orally deliver small-molecule drugs that are poorly water-soluble. ASDs consist of drug molecules in the amorphous form which are dispersed in a hydrophilic polymer matrix. Producing a high-performance ASD is critical for effective drug delivery and depends on many factors such as solubility of the drug in the matrix and the rate of drug release in aqueous medium (dissolution), which is linked to bioperformance. Often, researchers perform a large number of design iterations to achieve this objective. A detailed molecular-level understanding of the mechanisms behind ASD dissolution behavior would aid in the screening, designing, and optimization of ASD formulations and would minimize the need for testing a wide variety of prototype formulations. Molecular dynamics and related types of simulations, which model the collective behavior of molecules in condensed phase systems, can provide unique insights into these mechanisms. To study the effectiveness of these simulation techniques in ASD formulation dissolution, we carried out dissipative particle dynamics simulations, which are particularly an efficient form of molecular dynamics calculations. We studied two stages of the dissolution process: the early-stage of the dissolution process, which focuses on the dissolution at the ASD/water interface, and the late-stage of the dissolution process, where significant drug release would have occurred and there would be a mixture of drug and polymer molecules in a predominantly aqueous environment. Experimentally, we used Fourier transform infrared spectroscopy to study the interactions between drugs, polymers, and water in the dry and wet states and the chromatographic technique to study the rate of drug and polymer release. Both experiments and simulations provided evidence of polymer microstructures and drug-polymer interactions as important factors for the dissolution behavior of the investigated ASDs, consistent with previous work by Pudlas et al. (Eur. J. Pharm. Sci.2015, 67, 21-31). As experimental and simulation results are consistent and complementary, it is clear that there is significant potential for combined experimental and computational research for a detailed understanding of ASD formulations and, hence, formulation optimization.

Design of Organic Electronic Materials With a Goal-Directed Generative Model Powered by Deep Neural Networks and High-Throughput Molecular Simulations.

In recent years, generative machine learning approaches have attracted significant attention as an enabling approach for designing novel molecular materials with minimal design bias and thereby realizing more directed design for a specific materials property space. Further, data-driven approaches have emerged as a new tool to accelerate the development of novel organic electronic materials for organic light-emitting diode (OLED) applications. We demonstrate and validate a goal-directed generative machine learning framework based on a recurrent neural network (RNN) deep reinforcement learning approach for the design of hole transporting OLED materials. These large-scale molecular simulations also demonstrate a rapid, cost-effective method to identify new materials in OLEDs while also enabling expansion into many other verticals such as catalyst design, aerospace, life science, and petrochemicals.

Automated Transition State Search and Its Application to Diverse Types of Organic Reactions.

Transition state search is at the center of multiple types of computational chemical predictions related to mechanistic investigations, reactivity and regioselectivity predictions, and catalyst design. The process of finding transition states in practice is, however, a laborious multistep operation that requires significant user involvement. Here, we report a highly automated workflow designed to locate transition states for a given elementary reaction with minimal setup overhead. The only essential inputs required from the user are the structures of the separated reactants and products. The seamless workflow combining computational technologies from the fields of cheminformatics, molecular mechanics, and quantum chemistry automatically finds the most probable correspondence between the atoms in the reactants and the products, generates a transition state guess, launches a transition state search through a combined approach involving the relaxing string method and the quadratic synchronous transit, and finally validates the transition state via the analysis of the reactive chemical bonds and imaginary vibrational frequencies as well as by the intrinsic reaction coordinate method. Our approach does not target any specific reaction type, nor does it depend on training data; instead, it is meant to be of general applicability for a wide variety of reaction types. The workflow is highly flexible, permitting modifications such as a choice of accuracy, level of theory, basis set, or solvation treatment. Successfully located transition states can be used for setting up transition state guesses in related reactions, saving computational time and increasing the probability of success. The utility and performance of the method are demonstrated in applications to transition state searches in reactions typical for organic chemistry, medicinal chemistry, and homogeneous catalysis research. In particular, applications of our code to Michael additions, hydrogen abstractions, Diels-Alder cycloadditions, carbene insertions, and an enzyme reaction model involving a molybdenum complex are shown and discussed.

Successful application of the DBLOC method to the hydroxylation of camphor by cytochrome p450.

The activation barrier for the hydroxylation of camphor by cytochrome P450 was computed using a mixed quantum mechanics/molecular mechanics (QM/MM) model of the full protein-ligand system and a fully QM calculation using a cluster model of the active site at the B3LYP/LACVP*/LACV3P** level of theory, which consisted of B3LYP/LACV3P** single point energies computed at B3LYP/LACVP* optimized geometries. From the QM/MM calculation, a barrier height of 17.5 kcal/mol was obtained, while the experimental value was known to be less than or equal to 10 kcal/mol. This process was repeated using the D3 correction for hybrid DFT in order to investigate whether the inadequate treatment of dispersion interaction was responsible for the overestimation of the barrier. While the D3 correction does reduce the computed barrier to 13.3 kcal/mol, it was still in disagreement with experiment. After application of a series of transition metal optimized localized orbital corrections (DBLOC) and without any refitting of parameters, the barrier was further reduced to 10.0 kcal/mol, which was consistent with the experimental results. The DBLOC method to CH bond activation in methane monooxygenase (MMO) was also applied, as a second, independent test. The barrier in MMO was known, by experiment, to be 15.4 kcal/mol. After application of the DBLOC corrections to the MMO barrier compute by B3LYP, in a previous study, and accounting for dispersion with Grimme's D3 method, the unsigned deviation from experiment was improved from 3.2 to 2.3 kcal/mol. These results suggested that the combination of dispersion plus localized orbital corrections could yield significant quantitative improvements in modeling the catalytic chemistry of transition-metal containing enzymes, within the limitations of the statistical errors of the model, which appear to be on the order of approximately 2 kcal/mole.

Accurate pKa prediction in first-row hexaaqua transition metal complexes using the B3LYP-DBLOC method.

Acid dissociation constants are computed with density functional theory (DFT) for a series of ten first-row octahedral hexaaqua transition metal complexes at the B3LYP/LACV3P** level of theory. These results are then scaled, primarily to correct for basis set effects (as in previous work on predicting pKa's in organic systems1-5). Finally, localized orbital corrections (LOCs), developed by fitting properties such as ionization potentials, electron affinities, and ligand removal energies in prior publications,3,4,6,7 are applied without any further parameter adjustment. The combination of a single scale factor with the DBLOC (localized orbital corrections for first row transition metals) corrections (and thus a single adjustable parameter in all) improves the mean unsigned error from 5.7 pKa units (with no parameters) to 0.9 pKa units (maximum error 2.2 pKa units), which is close to chemical accuracy for this type of system. These results provide further encouragement with regard to the ability of the B3LYP-DBLOC model to provide accurate and robust results for DFT calculations on transition metal containing species.

Realistic cluster modeling of electron transport and trapping in solvated TiO2 nanoparticles.

We have developed a cluster model of a TiO(2) nanoparticle in the dye-sensitized solar cell and used first-principles quantum chemistry, coupled with a continuum solvation model, to compute structures and energetics of key electronic and structural intermediates and transition states. Our results suggest the existence of shallow surface trapping states induced by small cations and continuum solvent effect as well as the possibility of the existence of a surface band which is 0.3-0.5 eV below the conduction band edge. The results are in uniformly good agreement with experiment and establish the plausibility of an ambipolar model of electron diffusion in which small cations, such as Li(+), diffuse alongside the current carrying electrons in the device, stabilizing shallowing trapping states, facilitating diffusion from one of these states to another, in a fashion that is essential to the functioning of the cell.

A B3LYP-DBLOC empirical correction scheme for ligand removal enthalpies of transition metal complexes: parameterization against experimental and CCSD(T)-F12 heats of formation.

Average ligand removal enthalpies of 30 differently coordinated mono-nuclear fourth-row transition metal complexes taken from a database recently considered by Johnson and Becke [Can. J. Chem., 2009, 8, 1369] have been computed in the gas phase using unrestricted pseudo-spectral (LACV3P) and fully analytic (qzvp(-g)) B3LYP including a recently developed empirical dispersion correction. Heats of formation of neutral singlet reactants and neutral, potentially high spin, products have been taken from NIST's Organometallic Thermochemistry Database. Comparison of B3LYP-MM//qzvp(-g) and experimental average ligand removal enthalpies reveals a systematic error in the reported experimental enthalpies for manganese-containing complexes which is verified with high-level, CCSD(T)-F12//family of cc-pVTZ, explicitly correlated coupled-cluster methods. Other B3LYP-MM//qzvp(-g) error patterns give rise to a d-block localized orbital correction (DBLOC) scheme containing six transferable parameters that correct the functional's description of metal-ligand bonding, cation-π, and dispersion interactions as well as metal and/or ligand multi-reference effects. Metal-ligand cation-π and dispersion interactions have been fit to the monopole/induced-dipole, C(4)/R(4), and induced-dipole/induced-dipole, C(6)/R(6), interaction functions, respectively. This DBLOC model has been built upon a previously determined set of metal atom parameters which are necessary to properly describe the free metal atom reaction products. The final DBLOC model brings the mean unsigned error of B3LYP-MM//qzvp(-g) from 3.74 ± 3.51 kcal/mol to 0.94 ± 0.68 kcal/mol and corrects the functional's under binding in nearly every case. Several important connections among DBLOC parameters have been made.

Development of Accurate DFT Methods for Computing Redox Potentials of Transition Metal Complexes: Results for Model Complexes and Application to Cytochrome P450.

Single-electron reduction half potentials of 95 octahedral fourth-row transition metal complexes binding a diverse set of ligands have been calculated at the unrestricted pseudospectral B3LYP/LACV3P level of theory in a continuum solvent. Through systematic comparison of experimental and calculated potentials, it is determined that B3LYP strongly overbinds the d-manifold when the metal coordinates strongly interacting ligands and strongly underbinds the d-manifold when the metal coordinates weakly interacting ligands. These error patterns give rise to an extension of the localized orbital correction (LOC) scheme previously developed for organic molecules and which was recently extended to the spin-splitting properties of organometallic complexes. Mean unsigned errors in B3LYP redox potentials are reduced from 0.40 ± 0.20 V (0.88 V max error) to 0.12 ± 0.09 V (0.34 V max error) using a simple seven-parameter model. Although the focus of this article is on redox properties of transition metal complexes, we have found that applying our previous spin-splitting LOC model to an independent test set of oxidized and reduced complexes that are also spin-crossover complexes correctly reverses the ordering of spin states obtained with B3LYP. Interesting connections are made between redox and spin-splitting parameters with regard to the spectrochemical series and in their combined predictive power for properly closing the thermodynamic cycle of d-electron transitions in a transition metal complex. Results obtained from our large and diverse databases of spin-splitting and redox properties suggest that, while the error introduced by single reference B3LYP for simple multireference systems, like mononuclear transition metal complexes, remains significant, at around 2-5 kcal/mol, the dominant error, at around 10-20 kcal/mol, is in B3LYP's prediction of metal-ligand binding. Application of the LOC scheme to the rate-determining hydrogen atom transfer step in substrate hydroxylation by cytochrome P450 shows that this approach is able to correct the B3LYP barriers in comparison to recent kinetics experiments.

Accurate Force Field Development for Modeling Conjugated Polymers.

The modeling of the conformational properties of conjugated polymers entails a unique challenge for classical force fields. Conjugation imposes strong constraints upon bond rotation. Planar configurations are favored, but the concomitantly shortened bond lengths result in moieties being brought into closer proximity than usual. The ensuing steric repulsions are particularly severe in the presence of side chains, straining angles, and stretching bonds to a degree infrequently found in nonconjugated systems. We herein demonstrate the resulting inaccuracies by comparing the LMP2-calculated inter-ring torsion potentials for a series of substituted stilbenes and bithiophenes to those calculated using standard classical force fields. We then implement adjustments to the OPLS-2005 force field in order to improve its ability to model such systems. Finally, we show the impact of these changes on the dihedral angle distributions, persistence lengths, and conjugation length distributions observed during molecular dynamics simulations of poly[2-methoxy-5-(2'-ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV) and poly 3-hexylthiophene (P3HT), two of the most widely used conjugated polymers.

Systematic investigation of the catalytic cycle of a single site ruthenium oxygen evolving complex using density functional theory.

The mechanism of water oxidation by a single site ruthenium oxygen evolving complex is investigated using fully unrestricted pseudospectral B3LYP with the effective core potential LACV3P in continuum solvent with some quantum mechanical waters. Guess wave functions have been used that allow greater flexibility in sampling different electronic configurations of the complex. Systematic comparison with experiment is improved using these guesses because they provide a complete analysis of the low energy manifold and help to alleviate the formal disconnect between theory and experiment in assigning Lewis structures for transition metal complexes. In agreement with results from the literature, the challenging 4e(-)and 4H(+) oxidation of water is accomplished using a mechanism that features three proton coupled electron transfers, one electron transfer, one atom proton transfer (APT), and one ligand exchange (LE). Calculations on a large database of ruthenium complexes allows us to benchmark the computation of reduction half potentials and free energies of activation and to investigate systematic ligand variations and their effect on the reaction mechanism. Mean unsigned errors of reduction half potentials in comparison to experiment are generally small (100-200 mV). The APT and LE steps are found to be rate limiting with free energy barriers of 19.27 and 19.53 kcal/mol respectively, which is in excellent agreement with the ∼20 kcal/mol barrier obtained from experimental rate constants using classical transition state theory.

Correcting Systematic Errors in DFT Spin-Splitting Energetics for Transition Metal Complexes.

Spin-splittings of 57 octahedral first-row transition metal complexes calculated with B3LYP are compared with a database of experimental spectra collected from the literature. A variety of transition metal centers in various oxidation states and multiplicities along with a number of different coordinating ligands are considered. Environmental effects have been included to enable reasonable quantitative comparison with experiment. The manifold of states is studied using initial guesses constructed from ligand field theory. A localized orbital correction (LOC) model, referred to as DBLOC-DFT (d-block localized orbital corrected density functional theory), systematically corrects B3LYP calculations using five parameters. The final results are a considerable improvement over conventional DFT, bringing the mean unsigned error (MUE) from 10.14 kcal/mol with a standard deviation of 4.56 to 1.98 kcal/mol with a standard deviation of 1.62. Depending on the relative multiplicities of the ground and excited states, it is shown that B3LYP*, which has 15% exact nonlocal exchange, can lead to larger errors with respect to experiment than B3LYP. Application to 7 complexes from Swart et al. [ J. Phys. Chem. A 2004 , 108 , 5479. ] and 14 small-gap spin-crossover complexes, from the literature, shows the DBLOC model provides good agreement with a variety of experimental data.

Transferability in the natural linear-scaled coupled-cluster effective Hamiltonian approach: Applications to dynamic polarizabilities and dispersion coefficients.

A natural linear-scaled coupled-cluster (CC) method has been developed to calculate the response properties of large molecules, for example, dynamic polarizabilities and dispersion coefficients. The method is based on the transferability of the CC effective Hamiltonian from the equation-of-motion (EOM)-CC methods, subject to its representation in terms of highly transferable natural localized molecular orbitals. This transferability allows the interactions among regions in a molecule to be classified according to their important inter-region excitations and de-excitations. Dynamic polarizabilities determined in this way provide insight into calculating the excited states of large molecules using localized orbital concepts. Dispersion coefficients for the interactions within large molecules can be similarly determined. These could be useful in constructing corrective long-range potentials. Applications to alkanes, tryptophan, and polyglycine are presented. For those cases which are possible, conventional results can be reproduced. Dynamic polarizabilities of tryptophan indicate that the first excited state is localized to the indole group, while the second is localized to the carboxyl group.

Natural linear-scaled coupled-cluster theory with local transferable triple excitations: applications to peptides.

The natural linear-scaled coupled-cluster (NLSCC) method ( Flocke, N.; Bartlett, R. J. J. Chem. Phys. 2004, 121, 10935 ) is extended to include approximate triple excitations via a coupled-cluster with single, double, and triple excitation method (CCSDT-3). The triples contribution can potentially be embedded in a larger singles and doubles region. NLSCC exploits the extensivity of the CC wave function to represent it in terms of transferable natural localized molecular orbitals (NLMOs) or functional groups thereof that are obtained from small quantum mechanical (QM) regions. Both occupied and virtual NLMOs are local because they derive from the single-particle density matrix. Noncanonical triples amplitudes are avoided by applying the unitary localization matrix to the canonical CC wave function for a QM region. A generalized NLMO code interfaced to the ACES II quantum chemistry software package provides NLMOs for the relevant number of atoms in a given functional group. Applications include linear polyglycine and the pentapeptide met-enkephalin, which was chosen as a more realistic three-dimensional system with nontrivial side chains. The results show that the triples contributions are quite large for aromatic bonds suggesting an interesting active space method for triples in which different bonds require different excitation levels. The NLSCC approach recovers a very large percentage (>99%) of the CCSD or CCSDT-3 correlation energy.

Inhibitors tethered near the acetylcholinesterase active site serve as molecular rulers of the peripheral and acylation sites.

The acetylcholinesterase (AChE) active site consists of a narrow gorge with two separate ligand binding sites: an acylation site (or A-site) at the bottom of the gorge where substrate hydrolysis occurs and a peripheral site (or P-site) at the gorge mouth. AChE is inactivated by organophosphates as they pass through the P-site and phosphorylate the catalytic serine in the A-site. One strategy to protect against organophosphate inactivation is to design cyclic ligands that will bind specifically to the P-site and block the passage of organophosphates but not acetylcholine. To accelerate the process of identifying cyclic compounds with high affinity for the AChE P-site, we introduced a cysteine residue near the rim of the P-site by site-specific mutagenesis to generate recombinant human H287C AChE. Compounds were synthesized with a highly reactive methanethiosulfonyl substituent and linked to this cysteine through a disulfide bond. The advantages of this tethering were demonstrated with H287C AChE modified with six compounds, consisting of cationic trialkylammonium, acridinium, and tacrine ligands with tethers of varying length. Modification by ligands with short tethers had little effect on catalytic properties, but longer tethering resulted in shifts in substrate hydrolysis profiles and reduced affinity for acridinium affinity resin. Molecular modeling calculations indicated that cationic ligands with tethers of intermediate length bound to the P-site, whereas those with long tethers reached the A-site. These binding locations were confirmed experimentally by measuring competitive inhibition constants KI2 for propidium and tacrine, inhibitors specific for the P- and A-sites, respectively. Values of KI2 for propidium increased 30- to 100-fold when ligands had either intermediate or long tethers. In contrast, the value of KI2 for tacrine increased substantially only when ligands had long tethers. These relative changes in propidium and tacrine affinities thus provided a sensitive molecular ruler for assigning the binding locations of the tethered cations.