Effective Fragment Potential Method for H‑Bonding: How To Obtain Parameters for Nonrigid Fragments

Accuracy of the effective fragment potential (EFP) method was explored for describing intermolecular interaction energies in three dimers with strong H-bonded interactions, formic acid, formamide, and formamidine dimers, which are a part of HBC6 database of noncovalent interactions. Monomer geometries in these dimers change significantly as a function of intermonomer separation. Several EFP schemes were considered, in which fragment parameters were prepared for a fragment in its gas-phase geometry or recomputed for each unique fragment geometry. Additionally, a scheme in which gas-phase fragment parameters are shifted according to relaxed fragment geometries is introduced and tested. EFP data are compared against the coupled cluster with single, double, and perturbative triple excitations (CCSD­(T)) method in a complete basis set (CBS) and the symmetry adapted perturbation theory (SAPT). All considered EFP schemes provide a good agreement with CCSD­(T)/CBS for binding energies at equilibrium separations, with discrepancies not exceeding 2 kcal/mol. However, only the schemes that utilize relaxed fragment geometries remain qualitatively correct at shorter than equilibrium intermolecular distances. The EFP scheme with shifted parameters behaves quantitatively similar to the scheme in which parameters are recomputed for each monomer geometry and thus is recommended as a computationally efficient approach for large-scale EFP simulations of flexible systems

Ground-State Charge Transfer: Lithium–Benzene and the Role of Hartree–Fock Exchange

Most approximations to the exchange-correlation functional of Kohn–Sham density functional theory lead to delocalization errors that undermine the description of charge-transfer phenomena. We explore how various approximate functionals and charge-distribution schemes describe ground-state atomic-charge distributions in the lithium–benzene complex, a model system of relevance to carbon-based supercapacitors. To understand the trends, we compare Hartree–Fock (HF) and correlated post-HF calculations, confirming that the HOMO–LUMO gap is narrower in semilocal functionals but widened by hybrid functionals with large fractions of HF exchange. For semilocal functionals, natural bond orbital (NBO) and Mulliken schemes yield opposite pictures of how charge transfer occurs. In PBE, for example, when lithium and benzene are <1.5 Å apart, NBO yields a positive charge on the lithium atom, but the Mulliken scheme yields a negative charge. Furthermore, the partial charges in conjugated materials depend on the interplay between the charge-distribution scheme employed and the underlying exchange-correlation functional, being critically sensitive to the admixture of HF exchange. We analyze and explain why this happens, discuss implications, and conclude that hybrid functionals with an admixture of about one-fourth of HF exchange are particularly useful in describing charge transfer in the lithium–benzene model

Triplet–Triplet Coupling in Chromophore Dimers: Theory and Experiment

Knowledge of triplet state energies and triplet–triplet (T–T) interactions in aggregated organic molecules is essential for understanding photochemistry and dynamics of many natural and artificial systems. In this work, we combine direct phosphorescence measurements of triplet state energies, which are challenging due to the spin-forbidden nature of respective transitions and applicable to only a limited number of systems, with quantum chemical computational tools that can provide valuable qualitative and quantitative information about triplet states of interacting molecules. Using hexatriene, protoporphyrin, pheophorbide, and chlorophyll dimers as model systems, we demonstrate a complicated dependence of T–T coupling on a relative orientation of chromophores, governed by a nodal structure of overlapping electronic wave functions, that modulates interpigment interactions by orders of magnitude. It is also shown that geometrical relaxation of the triplet state is one of the critical factors for predictive modeling of T–T interactions in molecular aggregates

Quantifying the Nearly Random Microheterogeneity of Aqueous <i>tert</i>-Butyl Alcohol Solutions Using Vibrational Spectroscopy

The microheterogeneous structure of aqueous tert-butyl alcohol (TBA) solutions is quantified by combining experimental, simulations, and theoretical results. Experimental Raman multivariate curve resolution (Raman-MCR) C–H frequency shift measurements are compared with predictions obtained using combined quantum mechanical and effective fragment potential (QM/EFP) calculations, as well as with molecular dynamics (MD), random mixture (RM), and finite lattice (FL) predictions. The results indicate that the microheterogeneous aggregation in aqueous TBA solutions is slightly less than that predicted by MD simulations performed using either CHARMM generalized force field (CGenFF) or optimized parameters for liquid simulations all atom (OPLS-AA) force fields but slightly more than that in a self-avoiding RM of TBA-like molecules. The results imply that the onset of microheterogeneity in aqueous solutions occurs when solute contact free energies are about an order of magnitude smaller than thermal fluctuations, thus suggesting a fundamental bound of relevance to biological self-assembly

Dispersion Interactions in QM/EFP

The dispersion energy term between quantum-mechanical (QM) and classical (represented by effective fragment potentials, EFP) subsystems is developed and implemented. A new formulation is based on long-range perturbation theory and uses dynamic polarizability tensors of the effective fragments and electric field integrals and orbital energies of the quantum-mechanical subsystem. No parametrization is involved. The accuracy of the QM–EFP dispersion energy is tested on a number of model systems; the average mean unsigned error is 0.8 kcal/mol or 13% with respect to the symmetry adapted perturbation theory on the S22 data set of noncovalent interactions. The computational cost of the dispersion energy computation is low compared to the self-consistent field calculation of the QM subsystem. The dispersion energy is sensitive to the level of theory employed for the QM part and to the electrostatic interactions in the system. The latter means that the dispersion interactions in the QM/EFP method are not purely two-body but have more complex many-body behavior

Accurate Prediction of Noncovalent Interaction Energies with the Effective Fragment Potential Method: Comparison of Energy Components to Symmetry-Adapted Perturbation Theory for the S22 Test Set

Noncovalent interactions play an important role in the stabilization of biological molecules. The effective fragment potential (EFP) is a computationally inexpensive ab initio-based method for modeling intermolecular interactions in noncovalently bound systems. The accuracy of EFP is benchmarked against the S22 and S66 data sets for noncovalent interactions [Jurečka, P.; Šponer, J.; Černý, J.; Hobza, P. <i>Phys. Chem. Chem. Phys.</i> <b>2006</b>, <i>8</i>, 1985; Řezáč, J.; Riley, K. E.; Hobza, P. <i>J. Chem. Theory Comput.</i> <b>2011</b>, <i>7</i>, 2427]. The mean unsigned error (MUE) of EFP interaction energies with respect to coupled-cluster singles, doubles, and perturbative triples in the complete basis set limit [CCSD­(T)/CBS] is 0.9 and 0.6 kcal/mol for S22 and S66, respectively, which is similar to the MUE of MP2 and SCS-MP2 for the same data sets, but with a greatly reduced computational expense. Moreover, EFP outperforms classical force fields and popular DFT functionals such as B3LYP and PBE, while newer dispersion-corrected functionals provide a more accurate description of noncovalent interactions. Comparison of EFP energy components with the symmetry-adapted perturbation theory (SAPT) energies for the S22 data set shows that the main source of errors in EFP comes from Coulomb and polarization terms and provides a valuable benchmark for further improvements in the accuracy of EFP and force fields in general

Phase Behavior of Drug-Hydroxypropyl Methylcellulose Amorphous Solid Dispersions Produced from Various Solvent Systems: Mechanistic Understanding of the Role of Polymer using Experimental and Theoretical Methods

The vast majority of studies evaluating amorphous solid dispersions (ASDs) utilize solvent evaporation techniques as the preparation method. However, the impact of the solvent/cosolvent system properties on the polymer conformation and the phase behavior of the resultant drug/polymer blends is poorly understood. Herein, we investigate the influence of solvent properties on the phase behavior of ASDs containing itraconazole (ITZ) and hydroxypropylmethyl cellulose (HPMC) prepared using spin coating from binary/ternary cosolvent systems containing alkyl alcohols, dichloromethane (DCM), and water. The compatibility of the polymer with the cosolvent system was probed using high-resolution imaging techniques supported by molecular dynamics simulations. Solvent evaporation and evaporation rate profiles were tracked gravimetrically to understand the impact of the solvent composition on the evaporation process. Short-chain alcohols, including methanol (MeOH) and ethanol (EtOH), were found to induce drug-polymer demixing in the presence of water, with EtOH being less sensitive to moisture than MeOH owing to its ability to form an azeotrope with water. In contrast, water-induced mixing was observed when higher alcohols, including <i>n-</i>propanol (PrOH) and <i>n-</i>butanol (BuOH), were used as a cosolvent, due to the improved solubility of HPMC in the higher alcohols in the presence of water. Isopropanol (IPA) produced phase separated ASDs under wet and dry conditions with an increase in miscibility with faster evaporation rates in the presence of water. This solvent-triggered phase behavior highlights the importance of conducting a thorough screening of various solvents prior to the preparation of ASDs via solvent evaporation approaches such as spray drying

Mechanistic Design of Chemically Diverse Polymers with Applications in Oral Drug Delivery

Polymers play a key role in stabilizing amorphous drug formulations, a recent strategy employed to improve solubility and bioavailability of drugs delivered orally. However, the molecular mechanism of stabilization is unclear, therefore, the rational design of new crystallization-inhibiting excipients remains a substantial challenge. This article presents a combined experimental and computational approach to elucidate the molecular features that improve the effectiveness of cellulose polymers as solution crystallization inhibitors, a crucial first step toward their rational design. Polymers with chemically diverse substituents including carboxylic acids, esters, ethers, alcohols, amides, amines, and sulfides were synthesized. Measurements of nucleation induction times of the model drug, telaprevir, show that the only effective polymers contained carboxylate groups in combination with an optimal hydrocarbon chain length. Computational results indicate that polymer conformation as well as solvation free energy are important determinants of effectiveness at inhibiting crystallization and show that simulations are a promising predictive tool in the screening of polymers. This study suggests that polymers need to have an adequate hydrophilicity to promote solvation in an aqueous environment, and sufficient hydrophobic regions to drive interactions with the drug. Particularly, the right balance between key substituent groups and lengths of hydrocarbon side chains is needed to create effective materials

Thermodynamics and Kinetics for the Free Radical Oxygen Protein Oxidation Pathway in a Model for β‑Structured Peptides

Oxidative stress plays a role in many biological phenomena, but involved mechanisms and individual reactions are not well understood. Correlated electronic structure calculations with the MP2, MP4, and CCSD­(T) methods detail thermodynamic and kinetic information for the free radical oxygen protein oxidation pathway studied in a trialanine model system. The pathway includes aerobic, anaerobic and termination reactions. The course of the oxidation process depends on local conditions and availability of specific reactive oxygen species (ROS). A chemical mechanism is proposed for how oxidative stress promotes β-structure formation in the amyloid diseases. The work can be used to aid experimentalists as they explore individual reactions and mechanisms involving oxygen free radicals and oxidative stress in β-structured proteins

π-Hydrogen Bonding in Liquid Water

We report the experimental observation and quantitation of π-hydrogen bond formation between liquid water and benzene using Raman multivariate curve resolution (Raman-MCR) combined with quantum and classical (cluster and liquid) calculations. Our results establish that π-hydrogen bonds between liquid water and benzene are weaker and more flexible (have a more positive enthalpy and entropy) than bulk water hydrogen bonds. We further establish that such bonds also form between water and other aromatics, including the amino acid phenylalanine, thus implying their common occurrence at hydrated biological interfaces