Flexible boundary layer using exchange for embedding theories. I. Theory and implementation

Embedding theory is a powerful computational chemistry approach to exploring the electronic structure and dynamics of complex systems, with QM/MM being the prime example. A challenge arises when trying to apply embedding methodology to systems with diffusible particles, e.g. solvents, if some of them must be included in the QM region, for example in the description of solvent-supported electronic states or reactions involving proton transfer or charge-transfer-to-solvent: without a special treatment, inter-diffusion of QM and MM particles will lead eventually to a loss of QM/MM separation. We have developed a new method called Flexible Boundary Layer using Exchange (FlexiBLE) that solves the problem by adding a biasing potential to the system that closely maintains QM/MM separation. The method rigorously preserves ensemble averages by leveraging their invariance to exchange of identical particles. With a careful choice of the biasing potential, and the use of a tree algorithm to include only important QM and MM exchanges, we find the method has an MM-forcefield-like computational cost and thus adds negligible overhead to a QM/MM simulation. Furthermore, we show that molecular dynamics with the FlexiBLE bias conserves total energy and remarkably, dynamical quantities in the QM region are unaffected by the applied bias. FlexiBLE thus widens the range of chemistry that can be studied with embedding theory

Flexible boundary layer using exchange for embedding theories. II. QM/MM dynamics of the hydrated electron

The FlexiBLE embedding method introduced in the preceding companion paper [Z. Shen and W. J. Glover, J. Chem. Phys. X, X (2021)] is applied to explore the structure and dynamics of the aqueous solvated electron at an all-electron density functional theory QM/MM level. Compared to a one-electron mixed quantum/classical description, we find the dynamics of the many-electron model of the hydrated electron exhibits enhanced coupling to water OH stretch modes. Natural Bond Orbital analysis reveals this coupling is due to significant population of water OH σ* orbitals, reaching 20%. Based on this, we develop a minimal frontier orbital picture of the hydrated electron involving a cavity orbital and important coupling to 4-5 coordinating OH σ* orbitals. Implications for the interpretation of the spectroscopy of this interesting species are discussed

Regulation of dewetting and morphology evolution in spin-coated PS/PMMA blend films via graphene-based Janus nanosheets

Spin-coated blend films with complex phase-separated morphology find broad applications while precise tailoring of the morphology is still challenging. In this study, graphene oxide (GO)-based Janus nanosheets were synthesized by interfacial polymerization in a GO nanosheet stabilized Pickering emulsion with polystyrene (PS) and poly(hydroxyethyl methacrylate) synchronously being grafted to the GO nanosheet from the oil and water sides. The Janus nanosheets make the morphology of spin-coated PS/poly(methyl methacrylate)(PMMA) blend films tunable over the full height of the film until the substrate as their preferential assembly at the PS/PMMA interface and attachment on the glass substrate drive the top PS phase to migrate towards the substrate and the bottom PMMA phase to dewet from the substrate towards the air. By varying blend composition and Janus nanosheet loading, morphologies are readily transformed from a PS network on top of PMMA to PS droplets in the PMMA matrix and from PS encapsulated by PMMA to PMMA cavities in the PS network, etc.. This enables generating thin films with various morphologies ranging from a flat surface to cavity-network structures, droplet-matrix structures or bi-continuous structures, etc. at will. Moreover, the morphologies trapped by jammed nanosheets at the interface are super stable against further evolution upon annealing

Sex-specific associations of the urinary fourteen-metal mixture with NAFLD and liver fibrosis among US adults: A nationally representative study

Although previous studies have examined the hepatotoxicity of single metal exposure, the associations between metal mixture and non-alcoholic fatty liver disease (NAFLD) or fibrosis remain unclear. This study investigated the associations of urinary metal mixture with the risks of NAFLD and liver fibrosis in US adults using data from the National Health and Nutrition Examination Survey (NHANES) from 2017.01 to 2020.03. Vibration-controlled transient elastography was used to detect the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), which are indicators of NAFLD and liver fibrosis respectively. Three novel mixture modeling approaches including the Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) were used to estimate the associations of the urinary fourteen-metal mixture with Ln CAP and Ln LSM. There were 2283 adults aged over 18 years (1209 women and 1074 men) were included. Among women, urinary metal mixture was positively associated with Ln CAP in the BKMR and qgcomp models (both P  0.05). The metal mixture was not associated with Ln LSM in the three models regardless of genders (all P > 0.05). In conclusion, we observed sex-specific associations between urinary metal mixture and the prevalence of NAFLD in US adults. These findings emphasize the role of environmental heavy metal exposure in the development of NAFLD, and confirm the need for more prospective cohort studies on sex-specific manner

TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.</p

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic

Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in \u3e48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein–protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein–protein and protein–nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance