Trends in the impact of socioeconomic developments on polycyclic aromatic hydrocarbon concentrations in Dianchi Lake.

An analysis of the correlation between polycyclic aromatic hydrocarbons (PAHs) and economic parameters demonstrates that the total population, gross domestic product, coal consumption, petroleum, temperature, and day consumption significantly affect PAH concentrations in Dianchi Lake, Yunnan province, China. An artificial neural network (ANN) model was developed to predict the trend in PAH concentrations in the sediments of Dianchi Lake over the next 10 years based on current indicators of economic development. The ANN model estimated the concentration of PAHs from 1980 to 2014. The model was evaluated using available observations for the historical trends; concentrations of PAHs in the sediments of Dianchi Lake are calculated to be at 2128.1 ng/g in 2025 and are expected to decline up to 1044.3 ng/g by 2030. These concentrations are considered relatively high because of their impacts on the health of people and aquatic organisms and the development of surrounding industries. We show the importance of the socioeconomic and climate factors in increasing the pollution levels. Our results could support the local government to formulate effective measures to reduce the pollution levels in the lake.

Source analysis and influencing factors of historical changes in PAHs in the sediment core of Fuxian Lake, China.

In this study, the influencing factors and sources of historical changes in polycyclic aromatic hydrocarbons (PAHs) in the sediment core of Fuxian Lake were analyzed. Before 1970, the Σ16PAH concentration fluctuated widely, with one or more maximum values. During 1971-2004, the Σ16PAH concentration showed a slow growth trend, while during 2005-2017, the concentration increased sharply, reaching a peak value of 821 ng g-1. dw in 2017. The results of a positive matrix factorization (PMF) model demonstrated that before 1970, PAHs were mainly derived from biomass burning in the Fuxian Lake sediment core, with an overall contribution of 40 %. During 1971-2004, the source of PAHs was mainly coal combustion, with an overall contribution of 34 %. During 2005-2017, PAHs primarily originated from traffic, with an overall contribution of 33 %. Population, coal, GDP, motor, and petroleum had a significant influence on low molecular weight (LMW) PAHs in 1980-2004 and 2005-2017. Motor, coal, population, and GDP had a greater impact on high molecular weight (HMW) PAHs. Before 1970 and in 1971-2004, meteorological factors had little effect on PAHs in the sediment core in Fuxian Lake. During 2005-2017, day and rainfall were significantly negatively correlated with HMW PAHs, while temperature and wind were not correlated with PAH concentrations. During 2005-2017, total organic carbon (TOC) and total nitrogen (TN) had greater adsorption effects on HMW PAHs than on LMW PAHs. Before 1970 and in 1971-2004, the adsorption effects of TOC and TN on 3-4-ring PAHs were greater than those of 2-ring and 5-6-ring PAHs. Total phosphorus (TP) had no adsorption effect on PAHs in the entire sedimentary column.

Toward in vivo relevant drug design.

Current early and preclinical drug discovery are rooted in decades-old empirical principles describing structure-free energy and structure-function relationships under equilibrium conditions that frequently break down under in vivo conditions. Improved prediction of efficacy and toxicity depends on a paradigm shift to in vivo-relevant principles describing the true nonequilibrium/nonlinear dynamic (NLD) nature of cellular systems. Here, we outline a holistic, in vivo-relevant first principles theory ('Biodynamics'), in which cellular function/dysfunction, and pharmaco-/toxicodynamic effects are considered as emergent behaviors of multimolecular systems powered by covalent and noncovalent free energy sources. The reduction to practice of Biodynamics theory consists of in silico simulations performed at the atomistic and molecular systems levels, versus empirical models fit to in vitro data under the classical paradigm.

Probing the Dynamic Structure-Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory.

The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced Mpro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132-147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2-3 linker, alternately visiting two primary conformational states (denoted as M1 pro ↔ M2 pro); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137-Asn142) in response to domain 3 rotation and dimerization (denoted as M1/down pro ↔ 2·M2/up pro) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M1/down pro state, which promotes the M2/down pro state, dimerization (denoted as 2·M2/up pro-substrate), and catalysis. Here, we explore the state transitions of Mpro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions.

Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia.

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: The initial capture step: diffusion of a single fully solvated blocker copy into a large cavity lined by the intra-cellular cyclic nucleotide binding homology domain (CNBHD). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.The IKr disruption step: translocation of the captured blocker along the channel axis, such that: The head group, consisting of a quasi-rod-shaped moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface.One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost).Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region.A single captured blocker copy may conceivably associate and dissociate to/from the pore many times before exiting the CNBHD cavity. Lastly, we highlight possible flaws in the current hERG safety index (SI), and propose an alternate in vivo-relevant strategy factoring in: Benefit/risk.The predicted arrhythmogenic fractional hERG occupancy (based on action potential (AP) simulations of the undiseased human ventricular cardiomyocyte).Alteration of the safety threshold due to underlying disease.Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic (PK) variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.

Disturbance mechanisms of lacustrine organic carbon burial: Case study of Cuopu Lake, Southwest China.

Lakes are important organic carbon (OC) traps in the global carbon cycle. Recent studies have shown that the rate of OC burial in lacustrine sediments is influenced by factors such as climate change, land-use change, and eutrophication. In this study, we use multiproxy methods to reveal the mechanisms of lacustrine sediment OC burial in an alpine lake (Cuopu Lake), in southwest China. Combined with the dating from 210Pbex and n-alkanes distribution analysis using the Positive Matrix Factorization model, the sedimentary history was divided into five stages: religious activity (the 1840s-1880s), earthquake (the 1880s-1910s), garrison (the 1910s-1960s), transition (the 1960s-1990s), and ecotourism (the 1990s-2010s). During the earthquake stage, OC burial was dominated by terrestrial solids (>40%) and co-precipitated algae (>30%), with a rapid deposition rate (>4 mm a-1) and low OC concentration (<4 mg g-1). During the other stages, when the level of disturbance was relatively low, a change in nutrient conditions either promoted or inhibited plant growth, which influenced the type of buried OC. The contribution of OC derived from combustion sources varied from stage to stage. Severe anthropogenic disturbances have led to a significant increase in nutritional levels in the lake water, leading to an increase in the OC burial rate. Climate change, which leads to changes in temperature and rainfall, did not significantly influence OC burial, whereas nitrogen deposition (and associated ecological changes) was a significant determinant. When the general mechanism is dominant, the total nitrogen to inorganic phosphorus ratio is an effective indicator of OC burial due to its selective promotion of different plant types. In conclusion, our results suggest that lacustrine sediment OC burial is closely linked to physical and anthropogenic factors in Cuopu Lake, as well as similar montane lakes.

Sediment record of polycyclic aromatic hydrocarbons in Dianchi lake, southwest China: Influence of energy structure changes and economic development.

Sixteen polycyclic aromatic hydrocarbons (PAHs) in a sediment core from Dianchi Lake, southwest China, were analysed. The influence of changes in China's energy structure for 2-6 ringed PAHs was investigated to assess sources and the impact of socioeconomic development on temporal changes in concentrations. The concentration of the ΣPAH16 ranged from 746 to 2293 ng g-1. Prior to the 1960s relatively low concentrations of the ΣPAH16 and a larger proportion of 2-3-ring PAHs indicated that biomass combustion was the main source of PAHs. A rapid increase in the concentrations of 2-3 ring PAHs between 1975 and 2004 was attributed to population growth and coal consumption. A declining trend since 2004 was interpreted as being due to local changes in household energy usage. Increased concentrations of 4-ring PAH between 1975-2005 and 5-6-ring PAHs between the 1980s to 2004 showed correlations with increased coal consumption and the number of motor vehicles, respectively. These were caused by rapid urbanization and industrialization in the Dianchi watershed following the implementation of the Reform and Open Policy in 1978. A subsequent decline in the concentrations of 4-ring and 5-6-ring PAHs may have been due to decreased coal consumption and improvements in emission standards, respectively. Source apportionment by a PMF model revealed that coal combustion (29.2%), vehicle emissions (24.2%), petrogenic sources (21.8%), and biomass combustion (24.9%) were the sources of PAHs in the lake sediment core, and that coal combustion was the most important regional source of PAHs pollution.

Adaptive Markov state model estimation using short reseeding trajectories.

In the last decade, advances in molecular dynamics (MD) and Markov State Model (MSM) methodologies have made possible accurate and efficient estimation of kinetic rates and reactive pathways for complex biomolecular dynamics occurring on slow time scales. A promising approach to enhanced sampling of MSMs is to use "adaptive" methods, in which new MD trajectories are "seeded" preferentially from previously identified states. Here, we investigate the performance of various MSM estimators applied to reseeding trajectory data, for both a simple 1D free energy landscape and mini-protein folding MSMs of WW domain and NTL9(1-39). Our results reveal the practical challenges of reseeding simulations and suggest a simple way to reweight seeding trajectory data to better estimate both thermodynamic and kinetic quantities.

Reconciling Simulated Ensembles of Apomyoglobin with Experimental Hydrogen/Deuterium Exchange Data Using Bayesian Inference and Multiensemble Markov State Models.

Hydrogen/deuterium exchange (HDX) is a powerful technique to investigate protein conformational dynamics at amino acid resolution. Because HDX provides a measurement of solvent exposure of backbone hydrogens, ensemble-averaged over potentially slow kinetic processes, it has been challenging to use HDX protection factors to refine structural ensembles obtained from molecular dynamics simulations. This entails dual challenges: (1) identifying structural observables that best correlate with backbone amide protection from exchange and (2) restraining these observables in molecular simulations to model ensembles consistent with experimental measurements. Here, we make significant progress on both fronts. First, we describe an improved predictor of HDX protection factors from structural observables in simulated ensembles, parametrized from ultralong molecular dynamics simulation trajectory data, with a Bayesian inference approach used to retain the full posterior distribution of model parameters. We next present a new method for obtaining simulated ensembles in agreement with experimental HDX protection factors, in which molecular simulations are performed at various temperatures and restraint biases and used to construct multiensemble Markov State Models (MSMs). Finally, the BICePs (Bayesian Inference of Conformational Populations) algorithm is then used with our HDX protection factor predictor to infer which thermodynamic ensemble agrees best with the experiment and estimate populations of each conformational state in the MSM. To illustrate the approach, we use a combination of HDX protection factor restraints and chemical shift restraints to model the conformational ensemble of apomyoglobin at pH 6. The resulting ensemble agrees well with the experiment and gives insight into the all-atom structure of disordered helices F and H in the absence of heme.

A Maximum-Caliber Approach to Predicting Perturbed Folding Kinetics Due to Mutations.

We present a maximum-caliber method for inferring transition rates of a Markov state model (MSM) with perturbed equilibrium populations given estimates of state populations and rates for an unperturbed MSM. It is similar in spirit to previous approaches, but given the inclusion of prior information, it is more robust and simple to implement. We examine its performance in simple biased diffusion models of kinetics and then apply the method to predicting changes in folding rates for several highly nontrivial protein folding systems for which non-native interactions play a significant role, including (1) tryptophan variants of the GB1 hairpin, (2) salt-bridge mutations of the Fs peptide helix, and (3) MSMs built from ultralong folding trajectories of FiP35 and GTT variants of the WW domain. In all cases, the method correctly predicts changes in folding rates, suggesting the wide applicability of maximum-caliber approaches to efficiently predict how mutations perturb protein conformational dynamics.

Spherical monovalent ions at aqueous liquid-vapor interfaces: interfacial stability and induced interface fluctuations.

Ion-specific interfacial behaviors of monovalent halides impact processes such as protein denaturation, interfacial stability, and surface tension modulation, and as such, their molecular and thermodynamic underpinnings garner much attention. We use molecular dynamics simulations of monovalent anions in water to explore effects on distant interfaces. We observe long-ranged ion-induced perturbations of the aqueous environment, as suggested by experiment and theory. Surface stable ions, characterized as such by minima in potentials of mean force computed using umbrella sampling MD simulations, induce larger interfacial fluctuations compared to nonsurface active species, conferring more entropy approaching the interface. Smaller anions and cations show no interfacial potential of mean force minima. The difference is traced to hydration shell properties of the anions, and the coupling of these shells with distant solvent. The effects correlate with the positions of the anions in the Hofmeister series (acknowledging variations in force field ability to recapitulate essential underlying physics), suggesting how differences in induced, nonlocal perturbations of interfaces may be related to different specific-ion effects in dilute biophysical and nanomaterial systems.