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Non-alcoholic steatohepatitis (NASH) presents as an epidemic chronic liver disease that is closely associated with metabolic disorders and involves hepatic steatosis, inflammation, and fibrosis as key factors. Despite the enormous global prevalence of NASH, effective pharmacological interventions are lacking. Based on the hypothesis that the multifactorial condition NASH may benefit from combined multiple modes of action for enhanced therapeutic efficacy, we have previously developed dual FXR activators/sEH inhibitors (FXRa/sEHi) and observed remarkable antifibrotic effects upon their use in rodent NASH models. However, these first-generation FXRa/sEHi were characterized by moderate metabolic stability and short in vivo half-life. Aiming to overcome these pharmacokinetic drawbacks, we have systematically studied the structure-activity and structure-stability relationships of the chemotype and obtained second-generation FXRa/sEHi with improved pharmacokinetic parameters. With high plasma exposure, a half-life greater than 5 h, and similar dual potency on the intended targets, 13 presents as a substantially optimized FXRa/sEHi for late-stage preclinical development.The self-consistent coupled-perturbed (SC-CP) method in the CRYSTAL program has been adapted to obtain electromagnetic optical rotation properties of chiral periodic systems based on the calculation of the magnetic moment induced by the electric field. Toward that end, an expression for the magnetic transition moment is developed, which involves an appropriate electronic angular momentum operator. This operator is forced to be hermitian so that the chiroptical properties are real. In our formulation, the trace of the optical rotatory power matrix is gauge-origin-invariant as long as the electric dipole transition matrix elements are obtained using the velocity (rather than position) operator. selleck chemical On the other hand, the component along the optic axis is invariant in general for uniaxial and biaxial crystals. Under the same conditions, these properties also do not depend on the so-called missing integers that occur in the treatment of the electric dipole moment of quasi-one-dimensional periodic systems or the analogue of missing integers for the case of higher dimensionality. Tests on a model H2O2 polymer confirm the formalism and, as desired, show that the calculated properties are independent of the size and definition of the unit cell. In addition, an empirical relation to a finite oligomer gauge-including atomic orbital (GIAO) calculation is found. Applications, with comparison to experiment, are carried for α-quartz, tartaric acid crystal, and carbon nanotubes. Future developments of this initial approach to chiroptical properties in the solid state are noted.The native structure of a protein is stabilized by a number of interactions such as main-chain hydrogen bonds and side-chain hydrophobic contacts. However, it has been challenging to determine how these interactions contribute to protein stability at single amino acid resolution. Here, we quantified site-specific thermodynamic stability at the molecular level to extend our understanding of the stabilizing forces in protein folding. We derived the free energy components of individual amino acid residues separately for the folding of the human Pin WW domain based on simulated structures. A further decomposition of the thermodynamic properties into contributions from backbone and side-chain groups enabled us to identify the critical residues in the secondary structure and hydrophobic core formation, without introducing physical modifications to the system as in site-directed mutagenesis methods. By relating the structural and thermodynamic changes upon folding for each residue, we find that the simultaneous formation of the backbone hydrogen bonds and side-chain contacts cooperatively stabilizes the folded structure. The identification of stabilizing interactions in a folding protein at atomic resolution will provide molecular insights into understanding the origin of the protein structure and into engineering a more stable protein.The interaction of quantum light with matter like that inside a cavity is known to give rise to mixed light-matter states called polaritons. We discuss the impact of rotation of the cavity on the polaritons. It is shown that the number of polaritons increases because of this rotation. The structure of the original polaritons is modified, and new ones are induced by the rotation that strongly depend on the angular velocity and the choice of axis of rotation. In molecules the rotation can change the number of light-induced conical intersections and their dimensionality and hence strongly impact their quantum dynamics. General consequences are discussed.Diffusion Monte Carlo (DMC) provides a powerful method for understanding the vibrational landscape of molecules that are not well-described by conventional methods. The most computationally demanding step of these calculations is the evaluation of the potential energy. In this work, a general approach is developed in which a neural network potential energy surface is trained by using data generated from a small-scale DMC calculation. Once trained, the neural network can be evaluated by using highly parallelizable calls to a graphics processing unit (GPU). The power of this approach is demonstrated for DMC simulations on H2O, CH5+, and (H2O)2. The need to include permutation symmetry in the neural network potentials is explored and incorporated into the molecular descriptors of CH5+ and (H2O)2. It is shown that the zero-point energies and wave functions obtained by using the neural network potentials are nearly identical to the results obtained when using the potential energy surfaces that were used to train the neural networks at a substantial savings in the computational requirements of the simulations.Understanding the lateral organization in plasma membranes remains an open problem and is of great interest to many researchers. Model membranes consisting of coexisting domains are commonly used as simplified models of plasma membranes. The coarse-grained (CG) Martini force field has successfully captured spontaneous separation of ternary membranes into a liquid-disordered and a liquid-ordered domain. With all-atom (AA) models, however, phase separation is much harder to achieve due to the slow underlying dynamics. To remedy this problem, here, we apply the virtual site (VS) hybrid method on a ternary membrane composed of saturated lipids, unsaturated lipids, and cholesterol to investigate the phase separation. The VS scheme couples the two membrane leaflets at CG and AA resolution. We found that the rapid phase separation reached by the CG leaflet can accelerate and guide this process in the AA leaflet.