A Finite Element Solution of Lateral Periodic Poisson-Boltzmann Model for Membrane Channel Proteins.

Membrane channel proteins control the diffusion of ions across biological membranes. They are closely related to the processes of various organizational mechanisms, such as: cardiac impulse, muscle contraction and hormone secretion. Introducing a membrane region into implicit solvation models extends the ability of the Poisson-Boltzmann (PB) equation to handle membrane proteins. The use of lateral periodic boundary conditions can properly simulate the discrete distribution of membrane proteins on the membrane plane and avoid boundary effects, which are caused by the finite box size in the traditional PB calculations. In this work, we: (1) develop a first finite element solver (FEPB) to solve the PB equation with a two-dimensional periodicity for membrane channel proteins, with different numerical treatments of the singular charges distributions in the channel protein; (2) add the membrane as a dielectric slab in the PB model, and use an improved mesh construction method to automatically identify the membrane channel/pore region even with a tilt angle relative to the z-axis; and (3) add a non-polar solvation energy term to complete the estimation of the total solvation energy of a membrane protein. A mesh resolution of about 0.25 Å (cubic grid space)/0.36 Å (tetrahedron edge length) is found to be most accurate in linear finite element calculation of the PB solvation energy. Computational studies are performed on a few exemplary molecules. The results indicate that all factors, the membrane thickness, the length of periodic box, membrane dielectric constant, pore region dielectric constant, and ionic strength, have individually considerable influence on the solvation energy of a channel protein. This demonstrates the necessity to treat all of those effects in the PB model for membrane protein simulations

On TAML Catalyst Resting State Lifetimes:Kinetic, Mechanistic, and Theoretical Insight into Phosphate-Induced Demetalation of an Iron(III) Bis(sulfonamido)bis(amido)-TAML Catalyst

At ambient temperatures, neutral pH and ultralow concentrations (low nM), the bis(sulfonamido)bis(amido) oxidation catalyst [Fe{4-NO2C6H3-1,2-(NCOCMe2NSO2)2CHMe}(OH2)]− (1) has been shown to catalyze the addition of an oxygen atom to microcystin-LR. This persistent bacterial toxin can contaminate surface waters and render drinking water sources unusable when nutrient concentrations favor cyanobacterial blooms. In mechanistic studies of this oxidation, while the pH was controlled with phosphate buffers, it became apparent that iron ejection from 1 becomes increasingly problematic with increasing [phosphate] (0.3-1.0 M); 1 is not noticeably impacted at low concentrations (0.01 M). At pH &lt; 6.5 and [phosphate] ≥ 1.0 M, 1 decays quickly, losing iron from the macrocycle. Iron ejection is surprisingly mechanistically complex; the pseudo-first-order rate constant kobs has an unusual dependence on the total phosphate concentration ([Pt]), kobs = k1[Pt] + k2[Pt]2, indicating two parallel pathways that are first and second order in [phosphate], respectively. The pH profiles in the 5.5-8.3 range for k1 and k2 are different: bell-shaped with a maximum of around pH 7 for k1 and sigmoidal for k2 with higher values at lower pH. Mechanistic proposals for the k1 and k2 pathways are detailed based on both the kinetic data and density functional theory analysis. The major difference between k1 and k2 is the involvement of different phosphate species, i.e., HPO42- (k1) and H2PO4- (k2); HPO42- is less acidic but more nucleophilic, which favors intramolecular rate-limiting Fe-N bond cleavage. Instead, H2PO4- acts intermolecularly, where the kinetics suggest that [H4P2O8]2- drives degradation.</p

Estimating nitrogen and phosphorus concentrations in streams and rivers, within a machine learning framework.

Funder: University of Cambridge, Department of ZoologyFunder: NASA NNX17AI74GNitrogen (N) and Phosphorus (P) are essential nutritional elements for life processes in water bodies. However, in excessive quantities, they may represent a significant source of aquatic pollution. Eutrophication has become a widespread issue rising from a chemical nutrient imbalance and is largely attributed to anthropogenic activities. In view of this phenomenon, we present a new geo-dataset to estimate and map the concentrations of N and P in their various chemical forms at a spatial resolution of 30 arc-second (∼1 km) for the conterminous US. The models were built using Random Forest (RF), a machine learning algorithm that regressed the seasonally measured N and P concentrations collected at 62,495 stations across the US streams for the period of 1994-2018 onto a set of 47 in-house built environmental variables that are available at a near-global extent. The seasonal models were validated through internal and external validation procedures and the predictive powers measured by Pearson Coefficients reached approximately 0.66 on average

Estimating nitrogen and phosphorus concentrations in streams and rivers, within a machine learning framework.

Funder: University of Cambridge, Department of ZoologyFunder: NASA NNX17AI74GNitrogen (N) and Phosphorus (P) are essential nutritional elements for life processes in water bodies. However, in excessive quantities, they may represent a significant source of aquatic pollution. Eutrophication has become a widespread issue rising from a chemical nutrient imbalance and is largely attributed to anthropogenic activities. In view of this phenomenon, we present a new geo-dataset to estimate and map the concentrations of N and P in their various chemical forms at a spatial resolution of 30 arc-second (∼1 km) for the conterminous US. The models were built using Random Forest (RF), a machine learning algorithm that regressed the seasonally measured N and P concentrations collected at 62,495 stations across the US streams for the period of 1994-2018 onto a set of 47 in-house built environmental variables that are available at a near-global extent. The seasonal models were validated through internal and external validation procedures and the predictive powers measured by Pearson Coefficients reached approximately 0.66 on average

Hydrography90m: a new high-resolution global hydrographic dataset

The geographic distribution of streams and rivers drives a multitude of patterns and processes in hydrology, geomorphology, geography, and ecology. Therefore, a hydrographic network that accurately delineates both small streams and large rivers, along with their topographic and topological properties, with equal precision would be indispensable in the earth sciences. Currently, available global hydrographies do not feature small headwater streams in great detail. However, these headwaters are vital because they are estimated to contribute to more than 70 % of overall stream length. We aimed to fill this gap by using the MERIT Hydro digital elevation model at 3 arcsec (∼90 m at the Equator) to derive a globally seamless, standardised hydrographic network, the “Hydrography90m”, with corresponding stream topographic and topological information. A central feature of the network is the minimal upstream contributing area, i.e. flow accumulation, of 0.05 km2 (or 5 ha) to initiate a stream channel, which allowed us to extract headwater stream channels in great detail. By employing a suite of GRASS GIS hydrological modules, we calculated the range-wide upstream flow accumulation and flow direction to delineate a total of 1.6 million drainage basins and extracted globally a total of 726 million unique stream segments with their corresponding sub-catchments. In addition, we computed stream topographic variables comprising stream slope, gradient, length, and curvature attributes as well as stream topological variables to allow for network routing and various stream order classifications. We validated the spatial accuracy and flow accumulation of Hydrography90m against NHDPlus HR, an independent, national high-resolution hydrographic network dataset of the United States. Our validation shows that the newly developed Hydrography90m has the highest spatial precision and contains more headwater stream channels compared to three other global hydrographic datasets. This comprehensive approach provides a vital and long-overdue baseline for assessing actual streamflow in headwaters and opens new research avenues for high-resolution studies of surface water worldwide. Hydrography90m thus offers significant potential to facilitate the assessment of freshwater quantity and quality, inundation risk, biodiversity, conservation, and resource management objectives in a globally comprehensive and standardised manner. The Hydrography90m layers are available at https://doi.org/10.18728/igb-fred-762.1 (Amatulli et al., 2022a), and while they can be used directly in standard GIS applications, we recommend the seamless integration with hydrological modules in open-source QGIS and GRASS GIS software to further customise the data and derive optimal utility from it

The recovery of European freshwater biodiversity has come to a halt

Owing to a long history of anthropogenic pressures, freshwater ecosystems are among the most vulnerable to biodiversity loss1. Mitigation measures, including wastewater treatment and hydromorphological restoration, have aimed to improve environmental quality and foster the recovery of freshwater biodiversity2. Here, using 1,816 time series of freshwater invertebrate communities collected across 22 European countries between 1968 and 2020, we quantified temporal trends in taxonomic and functional diversity and their responses to environmental pressures and gradients. We observed overall increases in taxon richness (0.73% per year), functional richness (2.4% per year) and abundance (1.17% per year). However, these increases primarily occurred before the 2010s, and have since plateaued. Freshwater communities downstream of dams, urban areas and cropland were less likely to experience recovery. Communities at sites with faster rates of warming had fewer gains in taxon richness, functional richness and abundance. Although biodiversity gains in the 1990s and 2000s probably reflect the effectiveness of water-quality improvements and restoration projects, the decelerating trajectory in the 2010s suggests that the current measures offer diminishing returns. Given new and persistent pressures on freshwater ecosystems, including emerging pollutants, climate change and the spread of invasive species, we call for additional mitigation to revive the recovery of freshwater biodiversity.N. Kaffenberger helped with initial data compilation. Funding for authors and data collection and processing was provided by the EU Horizon 2020 project eLTER PLUS (grant agreement no. 871128); the German Federal Ministry of Education and Research (BMBF; 033W034A); the German Research Foundation (DFG FZT 118, 202548816); Czech Republic project no. P505-20-17305S; the Leibniz Competition (J45/2018, P74/2018); the Spanish Ministerio de Economía, Industria y Competitividad—Agencia Estatal de Investigación and the European Regional Development Fund (MECODISPER project CTM 2017-89295-P); Ramón y Cajal contracts and the project funded by the Spanish Ministry of Science and Innovation (RYC2019-027446-I, RYC2020-029829-I, PID2020-115830GB-100); the Danish Environment Agency; the Norwegian Environment Agency; SOMINCOR—Lundin mining & FCT—Fundação para a Ciência e Tecnologia, Portugal; the Swedish University of Agricultural Sciences; the Swiss National Science Foundation (grant PP00P3_179089); the EU LIFE programme (DIVAQUA project, LIFE18 NAT/ES/000121); the UK Natural Environment Research Council (GLiTRS project NE/V006886/1 and NE/R016429/1 as part of the UK-SCAPE programme); the Autonomous Province of Bolzano (Italy); and the Estonian Research Council (grant no. PRG1266), Estonian National Program ‘Humanitarian and natural science collections’. The Environment Agency of England, the Scottish Environmental Protection Agency and Natural Resources Wales provided publicly available data. We acknowledge the members of the Flanders Environment Agency for providing data. This article is a contribution of the Alliance for Freshwater Life (www.allianceforfreshwaterlife.org).Peer reviewe

Experimental and Theoretical Studies of TAML® Activators : Pharmaceuticals Degradation, Nuclear Tunneling and Electronic Structure Analysis

<p>Green chemistry concerns the scientific disciplines that support sustainability as their zenith. Sustainability has both temporal and spacial dimensions. The addition of the spacial dimension to it has significantly enhanced its visibility and horizon. Green chemistry, as an important subset of sustainability, radiates broadly and this entails a pursuer to choose their spectrum of interest. Therefore, I defined the technical domain of green chemistry from my perspective. Through projecting green chemistry onto the primary basis composed by the principle domain defined by Prof. Anastas and challenges domain interpreted by Prof. Collins and the technical domain by my definition, I mapped out my green chemistry trajectory. In a word, my Ph.D. training can be summarized as a research journey of combating persistent organic pollutants, characterizing the electronic signature of catalysts for renewable energy generation and catalytically oxidizing active pharmaceutical ingredients and hydrocarbons via a combinatorial avenues of computation, analysis and scientific inference. In view of the problem space of green chemistry, seeking renewable energies and eliminating persistent, disrupting or toxic compounds appear on the higher levels according to Prof. Collins. I attempted to tackle all the four problems to certain degrees during my Ph.D.</p> <p>Energy has propelled the engine of human civilization for hundreds of years. Today, the fossil fuels, the natural reserves we rely upon in the past, have approached their limit. More significantly, their continuing use shadows the sustainable future of human beings as well as the lives of all forms on this planet. An urgent need horizons for better ways to capture and convert solar energy to carbon neutral forms of chemical energy. The lesson from photosynthesis provides a promising answer — water splitting. To mimic this process, developing catalysts for water cleavage becomes the central theme. Among all the earth abundant and inexpensive elements, Co stands out for its high efficiency and dual capability of water reduction and oxidation. Between the two, water oxidation presents the major challenge. Co(IV) was shown to be the active intermediate in this chemical conversion. This highlights the importance of precise characterization of the electronic structure Co containing catalysts. To this end, I combined the spectroscopic information and DFT calculation to clarify the literature ambiguity in the diagnosis of Co containing complexes, and theoretically projects the avenue to acquire a Co(IV) electronic state in coordination complexes.</p> <p>The study of eliminating persistent organic pollutants was performed in the United Nations in the summer 2011. Apart from a technical summary of my research, I also identified two important causes that impasse on many environmental issues between nations. This signifies a global leadership that can unify and usher the international strength toward the sustainable summit.</p> <p>The research experience in the United Nations showed hydrocarbons and their halogenated derivatives are very resistant to natural attenuation. Then I started my fervent pursuit of hydrocarbon hydroxylation study via theoretical modeling. Comparing theoretical with experimental studies, the reaction rates of [Fe^V(O)(B*)]^–1 with ethylbenzene (EtBZ) and its isotope labeled species EtBZ-d10 differ in three respects: (i) the initial[Fe^V(O)(B*)]^–1 decay rate for the substrate EtBZ-d10 is slower than that for EtBZ, (ii) the slope of the ln (k/T) vs. 1/T plot of EtBZ-d10 is smaller than that for EtBZ over the experimental temperature range, and (iii) the extrapolated tangents of the kinetic curves give a large, negative intercept difference, Int(EtBZ) - Int(EtBZ-d10) < 0 at the limit 1/T → 0. Theoretical analysis, based on density functional theory calculations of thermodynamic parameters of the reaction species and Bell’s model for tunneling through quadratic barriers, shows that (i) and (ii) result from isotope-induced changes in both the zero-point energies and nuclear tunneling, whereas (iii) is exclusively an isotope mass effect on tunneling. The research result points out nuclear tunneling has a significant contribution to the hydrocarbon hydroxylation process. A theoretical model was proposed that can be used to predict absolute rate constants outside the experimental fathomable range</p> <p>In addition to persistent molecules, endocrine disrupting chemicals also deserve special attention. Active Pharmaceutical Ingredients (APIs) have been recognized as a hot-spot environmental pollutants largely due to their high disrupting potency. These anthropocentric synthetics compounds are mostly designed to aim at evolutionarily conserved targets to trigger biological responses at minute levels and optimized for extra degradation resistance for stable shelf lives. All these therapeutic benefits translate into ecotoxicity concerns when the parent compounds or their metabolites are released to the environment. A large body of literature has linked the exposure to APIs to Biological disasters. Under such a context, I applied TAML activators to treat to highly prescribed antidepressant drugs, Zoloft and Prozaic. The API for each is sertraline and fluoxetine.</p> <p>In the sertraline degradation study, I demonstrated that TAML activators at nanomolar concentrations in water activate hydrogen peroxide to rapidly degrade this persistent API. While all the API is readily consumed, degradation slows significantly at one intermediate, sertraline ketone. The process occurs from neutral to basic pH. The pathway has been characterized through four early intermediates which reflect the metabolism of sertraline, providing further evidence that TAML activator/peroxide reactive intermediates mimic those of cytochrome P450 enzymes. TAML catalysts have been designed to exhibit considerable variability in reactivity and this provides an excellent tool for observing degradation intermediates of widely differing stabilities. Two elusive, hydrolytically sensitive intermediates and likely human metabolites, sertraline imine and N-desmethylsertraline imine, could be identified only by using a fast-acting catalyst. The more stable intermediates and known human metabolites, desmethylsertraline and sertraline ketone, were most easily detected and studied using a slow-acting catalyst. The resistance of sertraline ketone to aggressive TAML activator/ peroxide treatment marks it as likely to be environmentally persistent and signals that its environmental effects are important components of the full implications of sertraline use.</p> <p>Fluoxetine, represents the first member of the serotonin receptor reuptake inhibitors (SSRIs) family and is one of the most successful among all members. Its top prescription record among SSRIs and extra stability leads to prevalent occurrence in the environment. Environmental studies showed that FLX can be toxic to aquatic species at trace level of exposure and disruptive to their neurosystems. Therefore, it is urgent to seek an environmentally friendly solution to diminish the harm FLX can potentially bring to the environment. Treatment with TAML activators and hydrogen peroxide, fluoxetine was shown to be rapidly degraded to harmless endpoints. An elusive intermediate along the degradation pathway was proposed and its fleet fate was studied using DFT calculations. The cascade breakdown feature of FLX under TAML®/H₂O₂ treatment inspires green pharmaceutical design.</p

Introducing Membrane Transport Energy into the Design of Sustainable Chemicals against Cytotoxicity

Adverse outcomes associated with chemical use and spill have raised concerns over its sustainability. The traditional toxicity testing, using laboratory animals as the downstream safety check, is becoming less viable due to the economical and ethical liabilities. Green chemistry proposed an alternative strategy to attain chemical sustainability: designing chemicals to maximize their intrinsic sustainability and thus minimize their hazardous risk. Following decades of progress, there is still a need to develop new metrics to quantify the level of chemical sustainability. In this report, we developed a new double functional tool capable of estimating the sustainability probability of a chemical and designing new chemicals to meet a desired sustainability probability. This tool was built upon the Naive Bayesian algorithm with the design variables stemming from three sources. Molecular softness and polarizability were derived from density functional theory (DFT), and membrane transport free energy was computed using our in-house developed finite element algorithm. Model validation against the cytotoxicity measured in the U.S. EPA Toxicity ForeCaster (ToxCast) database (tested up to 100 μM) yielded a score of 0.82 for the area under the curve (AUC) of the receiver operating characteristic (ROC). On the basis of this model, we constructed the assessment tool with the dual capabilities of prediction and design

On TAML Catalyst Resting State Lifetimes: Kinetic, Mechanistic, and Theoretical Insight into Phosphate-Induced Demetalation of an Iron(III) Bis(sulfonamido)bis(amido)-TAML Catalyst

At ambient temperatures, neutral pH and ultralow concentrations (low nM), the bis(sulfonamido)bis(amido) oxidation catalyst [Fe{4-NO2C6H3-1,2-(NCOCMe2NSO2)2CHMe}(OH2)]− (1) has been shown to catalyze the addition of an oxygen atom to microcystin-LR. This persistent bacterial toxin can contaminate surface waters and render drinking water sources unusable when nutrient concentrations favor cyanobacterial blooms. In mechanistic studies of this oxidation, while the pH was controlled with phosphate buffers, it became apparent that iron ejection from 1 becomes increasingly problematic with increasing [phosphate] (0.3–1.0 M); 1 is not noticeably impacted at low concentrations (0.01 M). At pH < 6.5 and [phosphate] ≥ 1.0 M, 1 decays quickly, losing iron from the macrocycle. Iron ejection is surprisingly mechanistically complex; the pseudo-first-order rate constant kobs has an unusual dependence on the total phosphate concentration ([Pt]), kobs = k1[Pt] + k2[Pt]2, indicating two parallel pathways that are first and second order in [phosphate], respectively. The pH profiles in the 5.5–8.3 range for k1 and k2 are different: bell-shaped with a maximum of around pH 7 for k1 and sigmoidal for k2 with higher values at lower pH. Mechanistic proposals for the k1 and k2 pathways are detailed based on both the kinetic data and density functional theory analysis. The major difference between k1 and k2 is the involvement of different phosphate species, i.e., HPO42– (k1) and H2PO4– (k2); HPO42– is less acidic but more nucleophilic, which favors intramolecular rate-limiting Fe–N bond cleavage. Instead, H2PO4– acts intermolecularly, where the kinetics suggest that [H4P2O8]2– drives degradation

Analysis of Hydrogen Atom Abstraction from Ethylbenzene by an Fe^VO(TAML) Complex

It was shown previously (<i>Chem. Eur. J</i>. <b>2015</b>, 21, 1803) that the rate of hydrogen atom abstraction, <i>k</i>, from ethylbenzene (EB) by TAML complex [Fe^V(O)­B*]⁻ (<b>1</b>) in acetonitrile exhibits a large kinetic isotope effect (KIE ∼ 26) in the experimental range 233–243 K. The extrapolated tangents of ln­(<i>k</i>/<i>T</i>) vs <i>T</i>^–1 plots for EB-<i>d</i>₁₀ and EB gave a large, negative intercept difference, Int­(EB) – Int­(EB-<i>d</i>₁₀) = −34.5 J mol^–1 K^–1 for <i>T</i>^–1 → 0, which is shown to be exclusively due to an isotopic mass effect on tunneling. A decomposition of the apparent activation barrier in terms of electronic, ZPE, thermal enthalpic, tunneling, and entropic contributions is presented. Tunneling corrections to Δ<i>H</i>^⧧ and Δ<i>S</i>^⧧ are estimated to be large. The DFT prediction, using functional B3LYP and basis set 6-311G, for the electronic contribution is significantly smaller than suggested by experiment. However, the agreement improves after correction for the basis set superposition error in the interaction between EB and <b>1</b>. The kinetic model employed has been used to predict rate constants outside the experimental temperature range, which enabled us to compare the reactivity of <b>1</b> with those of other hydrogen abstracting complexes