Development and Application of Hamiltonian Adaptive Resolution Simulations for Systems having Long-range Interactions

Computer simulations have proven to be a powerful tool in soft matter research since they have helped to elucidate microscopic details of many phenomena observed in experiments that would otherwise have remained unclear. Therefore, the high demand for computer simulations on one hand, and the emergence of very fast computational units on the other hand, have led to development of a great variety of computational methods. These techniques have provided the possibility to investigate phenomena occurring within a wide range of length and time scales, from chemical reactions at the quantum scale to self-assembly at the macroscale. However, the computational costs of studying these phenomena in a single, highly detailed resolution are often too expensive. Hence, provided the locality of the phenomenon, it is advantageous to develop multi-resolution techniques. In these approaches, the system is divided into a high resolution subregion, described by an accurate but computationally expensive model, and a low resolution region, where the rest of the system is treated by means of a coarse but computationally efficient model. One of such multi-resolution techniques is the Hamiltonian Adaptive Resolution Simulations (H-AdResS) method. In this approach, the two resolutions are smoothly coupled through a transition layer in which compensating forces are applied on the molecules, and a constant chemical potential throughout the resolutions is enforced. In this work, we first explain the challenges of implementing long-ranged elec- trostatic interactions in H-AdResS. We then propose and validate the usage of a short-range modification of Coulomb potential, the Damped Shifted Force model, in the context of the H-AdResS scheme. We validate this approach by reproducing the structural and dynamical properties of liquid water. Next, we take advantage of the constant chemical potential inherent to H-AdResS to introduce a new and efficient method to compute the chemical potential of liquids and mixtures. The method has been named spatially resolved thermodynamic integration (SPARTIAN). Subsequently, we employ the same approach to compute the free energy of solids by coupling the real crystals with their corresponding ideal Einstein crystals. Afterwards, we use the Jarzynski equality to obtain the solvation free energy of molecules by using steered molecular dynamics to pull the molecule from the atomistic (solvated state) into the ideal gas (unsolvated state) region. Lastly, we discuss the spatial block analysis (SBA) method to efficiently extrapolate thermodynamic quantities such as bulk isothermal compressibility from finite-size computer simulations, and discuss different types of finite-size effects in the SBA context. This study is designed to target the problems involving sampling in grand canonical ensembles which is also crucial for the extension and development of the SPARTIAN method into a new grand canonical molecular dynamics framework.Computersimulationen haben sich als leistungsfähiges Werkzeug zur Erforschung weicher Materie erwiesen, da sie geholfen haben zur Aufdeckung mikroskopischer Details vieler experimentell beobachteter Phänomene beizutragen, welche sonst unaufgeklärt geblieben wären. Demzufolge haben sowohl der hohe Bedarf an Computersimulationen, als auch die Entwicklung sehr schneller Computer zur Entwicklung einer groß en Vielfalt von Simulationsmethoden geführt. Diese Simulationstechniken haben die Möglichkeit geschaffen Phänomene zu untersuchen, welche auf einer groß en Bandbreite von Längen und Zeitskalen geschehen, angefangen bei chemischen Reaktionen auf der Quantenskala bis hin zur Selbstanordnung auf der Makroskala. Jedoch ist der Rechenaufwand, um diese Phänomene in einer einzigen hochdetaillierten Auflösung zu studieren oft zu groß. Daher ist es von Vorteil Simulationstechniken mit mehreren Auflösungen zu entwickeln, sofern die räumliche Abgegrenztheit des Phänomens gegeben ist. In diesen Methoden wird das System in einen hochaufgelösten Teilbereich, beschrieben durch ein genaues aber rechenaufwendiges Modell, und einen niedrigaufgelösten Teilbereich, beschrieben durch ein vergröbertes recheneffizientes Modell aufgeteilt, welcher den Rest des Systems beschreibt. Eine dieser Methoden mit mehreren Auflösungen ist die Methode der hamiltonisch adaptiv aufgelösten Simulationen (Hamiltonian Adaptive Resolution Simulations) (H-AdResS). In dieser Herangehensweise werden die beiden Teilbereiche verschiedener Auflösung glatt durch eine Übergangsschicht miteinander gekoppelt, in welcher Kompensationskräfte auf die Moleküle wirken. Dadurch wird ein durchgehend konstantes chemisches Potential erzwungen. In dieser Arbeit beschreiben wir als erstes die Herausforderungen, langreichweitige elektrostatische Wechselwirkungen in H-AdResS zu implementierchemen. Dann schlagen wir die Verwendung einer kurzreichweitigen Modifikation des Coulomb Potentials vor und validieren diese im Kontext des H-AdResS Schemas: das gedämpfte verschobene Kraft-Modell (Damped Shifted Force). Wir validieren diese Herangehensweise durch Reproduktion der strukturellen und dynamischen Eigenschaften von flüssigem Wasser. Als Nächstes benutzen wir das durchgehend konstante chemische Potential von H-AdResS, um eine neue und effiziente Methode einzufüren das chemische Potential von Flüssigkeiten und Mischungen zu berechnen. Diese Methode wurde räumlich aufgelöste thermodynamische Integration (spatially resolved thermodynamic integration) (SPARTIAN) genannt. Anschließ end wenden wir die gleiche Herangehensweise an, um die freie Energie von Festkörpern zu berechnen, in dem wir realistische Kristallmodelle mit den korrespondierenden idealen Einstein-Kristallen koppeln. Danach verwenden wir die Jarzynski-Gleichung, um die freie Lösungsenergie von Molekülen mittels Molekulardynamiksimulationen zu berechnen, in denen Moleküle gezielt vom atomistischen Teilbereich (gelöster Zustand) in den Teilbereich des idealen Gases (ungelöster Zustand) gezogen werden. Schließ lich diskutieren wir die räumlich aufgelöste Blockanalyse-Methode (spatial block analysis method) (SBA), um effizient thermodynamische Eigenschaften wie die isothermische Kompressibilität aus Computersimulationen von Systemen endlicher Größ e zu extrapolieren. Wir diskutieren verschiedene Arten von Effekten endlicher Systemgröß en im Zusammenhang der SBA-Methode. Dieser Teil der Arbeit ist daraufhin konzipiert, Sampling-Probleme groß kanonischer Ensembles anzugehen, was entscheidend ist für die Weiterentwicklung der SPARTIAN-Methode im Rahmen groß kanonischer Molekulardynamik-Simulationen.xiv, 161 Seite

Spatially Resolved Thermodynamic Integration: An Efficient Method to Compute Chemical Potentials of Dense Fluids

Many popular methods for the calculation of chemical potentials rely on the insertion of test particles into the target system. In the case of liquids and liquid mixtures, this procedure increases in difficulty upon increasing density or concentration, and the use of sophisticated enhanced sampling techniques becomes inevitable. In this work we propose an alternative strategy, spatially resolved thermodynamic integration, or SPARTIAN for short. Here, molecules are described with atomistic resolution in a simulation subregion, and as ideal gas particles in a larger reservoir. All molecules are free to diffuse between subdomains adapting their resolution on the fly. To enforce a uniform density profile across the simulation box, a single-molecule external potential is computed, applied, and identified with the difference in chemical potential between the two resolutions. Since the reservoir is represented as an ideal gas bath, this difference exactly amounts to the excess chemical potential of the target system. The present approach surpasses the high density/concentration limitation of particle insertion methods because the ideal gas molecules entering the target system region spontaneously adapt to the local environment. The ideal gas representation contributes negligibly to the computational cost of the simulation, thus allowing one to make use of large reservoirs at minimal expenses. The method has been validated by computing excess chemical potentials for pure Lennard-Jones liquids and mixtures, SPC and SPC/E liquid water, and aqueous solutions of sodium chloride. The reported results well reproduce literature data for these systems

Steering a solute between coexisting solvation states: Revisiting nonequilibrium work relations and the calculation of free energy differences

By analogy with single-molecule pulling experiments, we present a computational framework to obtain free energy differences between complex solvation states. To illustrate our approach, we focus on the calculation of solvation free energies (SFEs). However, the method can be readily extended to cases involving more complex solutes and solvation conditions as well as to the calculation of binding free energies. The main idea is to drag the solute across the simulation box where atomistic and ideal gas representations of the solvent coexist at constant temperature and chemical potential. At finite pulling speeds, the resulting work allows one to extract SFEs via nonequilibrium relations, whereas at infinitely slow pulling speeds, this process becomes equivalent to the thermodynamic integration method. Results for small molecules well agree with literature data and pave the way to systematic studies of arbitrarily large and complex molecules.By analogy with single-molecule pulling experiments, we present a computational framework to obtain free energy differences between complex solvation states. To illustrate our approach, we focus on the calculation of solvation free energies (SFEs). However, the method can be readily extended to cases involving more complex solutes and solvation conditions as well as to the calculation of binding free energies. The main idea is to drag the solute across the simulation box where atomistic and ideal gas representations of the solvent coexist at constant temperature and chemical potential. At finite pulling speeds, the resulting work allows one to extract SFEs via nonequilibrium relations, whereas at infinitely slow pulling speeds, this process becomes equivalent to the thermodynamic integration method. Results for small molecules well agree with literature data and pave the way to systematic studies of arbitrarily large and complex molecules

Visualizing the disordered nuclear transport machinery in situ

The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between the nucleus and cytosol1. The central channel of the NPC is filled with hundreds of intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs)2,3. Although the structure of the NPC scaffold has been resolved in remarkable detail, the actual transport machinery built up by FG-NUPs—about 50 MDa—is depicted as an approximately 60-nm hole in even highly resolved tomograms and/or structures computed with artificial intelligence4,5,6,7,8,9,10,11. Here we directly probed conformations of the vital FG-NUP98 inside NPCs in live cells and in permeabilized cells with an intact transport machinery by using a synthetic biology-enabled site-specific small-molecule labelling approach paired with highly time-resolved fluorescence microscopy. Single permeabilized cell measurements of the distance distribution of FG-NUP98 segments combined with coarse-grained molecular simulations of the NPC allowed us to map the uncharted molecular environment inside the nanosized transport channel. We determined that the channel provides—in the terminology of the Flory polymer theory12—a ‘good solvent’ environment. This enables the FG domain to adopt expanded conformations and thus control transport between the nucleus and cytoplasm. With more than 30% of the proteome being formed from IDPs, our study opens a window into resolving disorder–function relationships of IDPs in situ, which are important in various processes, such as cellular signalling, phase separation, ageing and viral entry

Mapping development and health effects of cooking with solid fuels in low-income and middle-income countries, 2000-18 : a geospatial modelling study

Background More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels.Methods We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km x 5 km resolution in 98 LMICs based on 2.1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution.Findings Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205000 (95% uncertainty interval 147000-257000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution.Interpretation Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe

Global, regional, and national burden of neurological disorders, 1990–2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background: Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. Methods: We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. Findings: Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable). Interpretation: Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Funding: Bill & Melinda Gates Foundation

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Background Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings Globally in 2019, 1.14 billion (95% uncertainty interval 1.13-1.16) individuals were current smokers, who consumed 7.41 trillion (7.11-7.74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27.5% [26. 5-28.5] reduction) and females (37.7% [35.4-39.9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0.99 billion (0.98-1.00) in 1990. Globally in 2019, smoking tobacco use accounted for 7.69 million (7.16-8.20) deaths and 200 million (185-214) disability-adjusted life-years, and was the leading risk factor for death among males (20.2% [19.3-21.1] of male deaths). 6.68 million [86.9%] of 7.69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation In the absence of intervention, the annual toll of 7.69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a dear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019 : A systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC