Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more ...effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.
DNA barcoding-type studies assemble single-locus data from large samples of individuals and species, and have provided new kinds of data for evolutionary surveys of diversity. An important goal of ...many such studies is to delimit evolutionarily significant species units, especially in biodiversity surveys from environmental DNA samples. The Generalized Mixed Yule Coalescent (GMYC) method is a likelihood method for delimiting species by fitting within- and between-species branching models to reconstructed gene trees. Although the method has been widely used, it has not previously been described in detail or evaluated fully against simulations of alternative scenarios of true patterns of population variation and divergence between species. Here, we present important reformulations to the GMYC method as originally specified, and demonstrate its robustness to a range of departures from its simplifying assumptions. The main factor affecting the accuracy of delimitation is the mean population size of species relative to divergence times between them. Other departures from the model assumptions, such as varying population sizes among species, alternative scenarios for speciation and extinction, and population growth or subdivision within species, have relatively smaller effects. Our simulations demonstrate that support measures derived from the likelihood function provide a robust indication of when the model performs well and when it leads to inaccurate delimitations. Finally, the so-called single-threshold version of the method outperforms the multiple-threshold version of the method on simulated data: we argue that this might represent a fundamental limit due to the nature of evidence used to delimit species in this approach. Together with other studies comparing its performance relative to other methods, our findings support the robustness of GMYC as a tool for delimiting species when only single-locus information is available.
A fundamental assumption in statistical physics is that generic closed quantum many-body systems thermalize under their own dynamics. Recently, the emergence of many-body localized systems has ...questioned this concept and challenged our understanding of the connection between statistical physics and quantum mechanics. Here we report on the observation of a many-body localization transition between thermal and localized phases for bosons in a two-dimensional disordered optical lattice. With our single-site–resolved measurements, we track the relaxation dynamics of an initially prepared out-of-equilibrium density pattern and find strong evidence for a diverging length scale when approaching the localization transition. Our experiments represent a demonstration and in-depth characterization of many-body localization in a regime not accessible with state-of-the-art simulations on classical computers.
ABSTRACT The late stages of terrestrial planet formation are dominated by giant impacts that collectively influence the growth, composition, and habitability of any planets that form. Hitherto, ...numerical models designed to explore these late stage collisions have been limited by assuming that all collisions lead to perfect accretion, and many of these studies lack the large number of realizations needed to account for the chaotic nature of N-body systems. We improve on these limitations by performing 280 simulations of planet formation around a Sun-like star, half of which used an N-body algorithm that has recently been modified to include fragmentation and hit-and-run (bouncing) collisions. We find that when fragmentation is included, the final planets formed are comparable in terms of mass and number; however, their collision histories differ significantly and the accretion time approximately doubles. We explored impacts onto Earth-like planets, which we parameterized in terms of their specific impact energies. Only 15 of our 164 Earth-analogs experienced an impact that was energetic enough to strip an entire atmosphere. To strip about half of an atmosphere requires energies comparable to recent models of the Moon-forming giant impact. Almost all Earth-analogs received at least one impact that met this criteria during the 2 Gyr simulations and the median was three giant impacts. The median time of the final giant impact was 43 Myr after the start of the simulations, leading us to conclude that the time-frame of the Moon-forming impact is typical among planetary systems around Sun-like stars.
One of the most important biological processes at the molecular level is the formation of protein-ligand complexes. Therefore, determining their structure and underlying key interactions is of ...paramount relevance and has direct applications in drug development. Because of its low cost relative to its experimental sibling, molecular dynamics (MD) simulations in the presence of different solvent probes mimicking specific types of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots. However, a systematic comparison of different probes and their real predictive power from a quantitative and thermodynamic point of view is still missing. In the present work, we have performed MD simulations of 18 different proteins in pure water as well as water mixtures of ethanol, acetamide, acetonitrile and methylammonium acetate, leading to a total of 5.4 μs simulation time. For each system, we determined the corresponding solvent sites, defined as space regions adjacent to the protein surface where the probability of finding a probe atom is higher than that in the bulk solvent. Finally, we compared the identified solvent sites with 121 different protein-ligand complexes and used them to perform molecular docking and ligand binding free energy estimates. Our results show that combining solely water and ethanol sites allows sampling over 70% of all possible protein-ligand interactions, especially those that coincide with ligand-based pharmacophoric points. Most important, we also show how the solvent sites can be used to significantly improve ligand docking in terms of both accuracy and precision, and that accurate predictions of ligand binding free energies, along with relative ranking of ligand affinity, can be performed.
•The impact of new Italian weather data on building simulation was analysed.•Two simulations were carried out with a dated and an up-dated dataset, for 52 locations.•Italian representative ...multifamily house models were used.•For each model, two cases were studied: uninsulated and insulated constructions.•The results highlight great differences in ideal energy.
Dynamic thermal simulation is attracting the interest of designers thanks to the availability of numerical codes. However, one of the main problems facing the potential users is hourly-weather data availability. In Italy, the main source for the data is drawn upon the IGDG database. It is provided by the EnergyPlus weather site and the related measurements were collected between 1951 and 1970. A new set of files, gathered between 1989 and 2014, has recently become available. Nevertheless, it needs additional work to be directly implemented in energy simulation codes, which can lead users to download and apply the already available IGDG database files. In order to evaluate the ensuing effects, 52 Italian weather file locations were selected, and two simulations were carried out on seven multifamily-house models considering the difference between the results obtained using the old and new weather data. Since the locations of the two databases do not coincide, a matching method was implemented. This paper compares the simulation results arising from the choice of the weather file pertaining to the two databases. The weather files were selected within a 50 km range and 50 m elevation difference, to minimize misrepresentative results due to different climatic conditions. The models are typical of the most widespread building typology of the Italian building stock. For each model, two building fabric types were considered, the former was poorly insulated, the latter was well insulated thanks to an advanced refurbishment activity. Simulations were carried out with the EnergyPlus software.
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