Model of a multiverse providing the dark energy of our universe

It is shown that the dark energy presently observed in our universe can be regarded as the energy of a scalar field driving an inflation-like expansion of a multiverse with ours being a subuniverse among other parallel universes. A simple model of this multiverse is elaborated: Assuming closed space geometry, the origin of the multiverse can be explained by quantum tunneling from nothing; subuniverses are supposed to emerge from local fluctuations of separate inflation fields. The standard concept of tunneling from nothing is extended to the effect that in addition to an inflationary scalar field, matter is also generated, and that the tunneling leads to an (unstable) equilibrium state. The cosmological principle is assumed to pertain from the origin of the multiverse until the first subuniverses emerge. With increasing age of the multiverse, its spatial curvature decays exponentially so fast that, due to sharing the same space, the flatness problem of our universe resolves by itself. The dark energy density imprinted by the multiverse on our universe is time-dependent, but such that the ratio $w{=}\varrho/(c^2p)$ of its mass density and pressure (times $c^2$) is time-independent and assumes a value $-1{+}\epsilon$ with arbitrary $\epsilon{>}0$. $\epsilon$ can be chosen so small, that the dark energy model of this paper can be fitted to the current observational data as well as the cosmological constant model.Comment: 32 pages, 4 figure

Characterization of Folding Mechanisms of Trp-Cage and WW-Domain by Network Analysis of Simulations with a Hybrid-Resolution Model

In this study, we apply a hybrid-resolution model, namely, PACE, to characterize the free energy surfaces (FESs) of Trp-cage and a WW-domain variant along with the respective folding mechanisms. Unbiased, independent simulations with PACE are found to achieve together multiple folding and unfolding events for both proteins, allowing us to perform network analysis of the FESs to identify folding pathways. PACE reproduces for both proteins expected complexity hidden in the folding FESs, in particular metastable non-native intermediates. Pathway analysis shows that some of these intermediates are, actually, on-pathway folding intermediates and that intermediates kinetically closest to the native states can be either critical on-pathway or off-pathway intermediates, depending on the protein. Apart from general insights into folding, specific folding mechanisms of the proteins are resolved. We find that Trp-cage folds via a dominant pathway in which hydrophobic collapse occurs before the N-terminal helix forms; full incorporation of Trp6 into the hydrophobic core takes place as the last step of folding, which, however, may not be the rate-limiting step. For the WW-domain variant studied, we observe two main folding pathways with opposite orders of formation of the two hairpins involved in the structure; for either pathway, formation of hairpin 1 is more likely to be the rate-limiting step. Altogether, our results suggest that PACE combined with network analysis is a computationally efficient and valuable tool for the study of protein folding

Further Optimization of a Hybrid United-Atom and Coarse-Grained Force Field for Folding Simulations: Improved Backbone Hydration and Interactions between Charged Side Chains

PACE, a hybrid force field that couples united-atom protein models with coarse-grained (CG) solvent (<i>J. Chem. Theory Comput.</i> <b>2010</b>, <i>6</i>, 3373), has been further optimized, aiming to improve its efficiency for folding simulations. Backbone hydration parameters have been reoptimized based on hydration free energies of polyalanyl peptides through atomistic simulations. Also, atomistic partial charges from all-atom force fields were combined with PACE to provide a more realistic description of interactions between charged groups. Using replica exchange molecular dynamics, ab initio folding using the new PACE has been achieved for seven small proteins (16–23 residues) with different structural motifs. Experimental data about folded states, such as their stability at room temperature, melting point, and nuclear magnetic resonance nuclear Overhauser effect constraints, were also well reproduced. Moreover, a systematic comparison of folding kinetics at room temperature has been made with experiments, through standard molecular dynamics simulations, showing that the new PACE may accelerate the actual folding kinetics 5–10-fold, permitting now the study of folding mechanisms. In particular, we used the new PACE to fold a 73-residue protein, α3D, in multiple 10–30 μs simulations, to its native states (C_α root-mean-square deviation of ∼0.34 nm). Our results suggest the potential applicability of the new PACE for the study of folding and dynamics of proteins

Fibril Elongation by Aβ_17–42: Kinetic Network Analysis of Hybrid-Resolution Molecular Dynamics Simulations

A critical step of β-amyloid fibril formation is fibril elongation in which amyloid-β monomers undergo structural transitions to fibrillar structures upon their binding to fibril tips. The atomic detail of the structural transitions remains poorly understood. Computational characterization of the structural transitions is limited so far to short Aβ segments (5–10 aa) owing to the long time scale of Aβ fibril elongation. To overcome the computational time scale limit, we combined a hybrid-resolution model with umbrella sampling and replica exchange molecular dynamics and performed altogether ∼1.3 ms of molecular dynamics simulations of fibril elongation for Aβ_17–42. Kinetic network analysis of biased simulations resulted in a kinetic model that encompasses all Aβ segments essential for fibril formation. The model not only reproduces key properties of fibril elongation measured in experiments, including Aβ binding affinity, activation enthalpy of Aβ structural transitions and a large time scale gap (τ_lock/τ_dock = 10³–10⁴) between Aβ binding and its structural transitions, but also reveals detailed pathways involving structural transitions not seen before, namely, fibril formation both in hydrophobic regions L17-A21 and G37-A42 preceding fibril formation in hydrophilic region E22-A30. Moreover, the model identifies as important kinetic intermediates strand–loop–strand (SLS) structures of Aβ monomers, long suspected to be related to fibril elongation. The kinetic model suggests further that fibril elongation arises faster at the fibril tip with exposed L17-A21, rather than at the other tip, explaining thereby unidirectional fibril growth observed previously in experiments

In Situ Generation of Palladium Nanoparticles: Ligand-Free Palladium Catalyzed Pivalic Acid Assisted Carbonylative Suzuki Reactions at Ambient Conditions

Highly selective carbonylative Suzuki reactions of aryl iodides with arylboronic acids using an in situ generated nanopalladium system furnished products in high yields. The reactions were performed under ambient conditions and in the absence of an added ligand. The key to success is the addition of pivalic acid, which can effectively suppress undesired Suzuki coupling. The synthesis can be easily scaled up, and the catalytic system can be reused up to nine times. The nature of the active catalytic species are discussed

Drying-Mediated Assembly of Colloidal Nanoparticles into Large-Scale Microchannels

Large-scale highly ordered microchannels were spontaneously and rapidly created by simply drying the colloidal nanoparticle suspension on a rigid substrate. Interestingly, free evaporation of colloidal suspension yielded radially aligned microchannels, while constrained evaporation that was rendered by the use of confined geometries composed of either two nearly parallel plates or a slide placed perpendicular to a rigid substrate imparted the formation of periodic arrays of parallel microchannels in a controllable manner. The microchannels were formed as a result of the competition between stress relaxation due to crack opening that ruptured the film and stress increase due to the loss of solvent. Quite intriguingly, these patterned microchannels can be exploited as templates to craft well-ordered metallic stripes. This facile and scalable approach may offer a new paradigm of producing microscopic patterns over large areas with unprecedented regularity at low cost that can serve as scaffolds for use in microelectronics and microfluidic-based biochips, among other areas

Drying-Mediated Assembly of Colloidal Nanoparticles into Large-Scale Microchannels

Large-scale highly ordered microchannels were spontaneously and rapidly created by simply drying the colloidal nanoparticle suspension on a rigid substrate. Interestingly, free evaporation of colloidal suspension yielded radially aligned microchannels, while constrained evaporation that was rendered by the use of confined geometries composed of either two nearly parallel plates or a slide placed perpendicular to a rigid substrate imparted the formation of periodic arrays of parallel microchannels in a controllable manner. The microchannels were formed as a result of the competition between stress relaxation due to crack opening that ruptured the film and stress increase due to the loss of solvent. Quite intriguingly, these patterned microchannels can be exploited as templates to craft well-ordered metallic stripes. This facile and scalable approach may offer a new paradigm of producing microscopic patterns over large areas with unprecedented regularity at low cost that can serve as scaffolds for use in microelectronics and microfluidic-based biochips, among other areas

Self-Assembly Pathways of β‑Sheet-Rich Amyloid-β(1–40) Dimers: Markov State Model Analysis on Millisecond Hybrid-Resolution Simulations

Early oligomerization during amyloid-β (Aβ) aggregation is essential for Aβ neurotoxicity. Understanding how unstructured Aβs assemble into oligomers, especially those rich in β-sheets, is essential but remains challenging as the assembly process is too transient for experimental characterization and too slow for molecular dynamics simulations. So far, atomic simulations are limited only to studies of either oligomer structures or assembly pathways for short Aβ segments. To overcome the computational challenge, we combine in this study a hybrid-resolution model and adaptive sampling techniques to perform over 2.7 ms of simulations of formation of full-length Aβ40 dimers that are the earliest toxic oligomeric species. The Markov state model is further employed to characterize the transition pathways and associated kinetics. Our results show that for two major forms of β-sheet-rich structures reported experimentally, the corresponding assembly mechanisms are markedly different. Hairpin-containing structures are formed by direct binding of soluble Aβ in β-hairpin-like conformations. Formation of parallel, in-register structures resembling fibrils occurs ∼100-fold more slowly and involves a rapid encounter of Aβ in arbitrary conformations followed by a slow structural conversion. The structural conversion proceeds via diverse pathways but always requires transient unfolding of encounter complexes. We find that the transition kinetics could be affected differently by intra-/intermolecular interactions involving individual residues in a conformation-dependent manner. In particular, the interactions involving Aβ’s N-terminal part promote the assembly into hairpin-containing structures but delay the formation of fibril-like structures, thus explaining puzzling observations reported previously regarding the roles of this region in the early assembly process

Comprehensive and Quantitative Profiling of the Human Sweat Submetabolome Using High-Performance Chemical Isotope Labeling LC–MS

Human sweat can be noninvasively collected and used as a media for diagnosis of certain diseases as well as for drug detection. However, because of very low concentrations of endogenous metabolites present in sweat, metabolomic analysis of sweat with high coverage is difficult, making it less widely used for metabolomics research. In this work, a high-performance method for profiling the human sweat submetabolome based on chemical isotope labeling (CIL) liquid chromatography–mass spectrometry (LC–MS) is reported. Sweat was collected using a gauze sponge style patch, extracted from the gauze by centrifugation, and then derivatized using CIL. Differential ¹²C- and ¹³C-dansylation labeling was used to target the amine/phenol submetabolome. Because of large variations in the total amount of sweat metabolites in individual samples, sample amount normalization was first performed using liquid chromatography with UV detection (LC–UV) after dansylation. The ¹²C-labeled individual sample was then mixed with an equal amount of ¹³C-labeled pooled sample. The mixture was subjected to LC–MS analysis. Over 2707 unique metabolites were detected across 54 sweat samples collected from six individuals with an average of 2002 ± 165 metabolites detected per sample from a total of 108 LC–MS runs. Using a dansyl standard library, we were able to identify 83 metabolites with high confidence; many of them have never been reported to be present in sweat. Using accurate mass search against human metabolome libraries, we putatively identified an additional 2411 metabolites. Uni- and multivariate analyses of these metabolites showed significant differences in the sweat submetabolomes between male and female, as well as between early and late exercise. These results demonstrate that the CIL LC–MS method described can be used to profile the human sweat submetabolome with high metabolomic coverage and high quantification accuracy to reveal metabolic differences in different sweat samples, thereby allowing the use of sweat as another human biofluid for comprehensive and quantitative metabolomics research

Initial Substrate Binding of γ‑Secretase: The Role of Substrate Flexibility

γ-Secretase cleaves transmembrane domains (TMD) of amyloid precursor protein (APP), producing pathologically relevant amyloid-β proteins. Initial substrate binding represents a key step of the γ-secretase cleavage whose mechanism remains elusive. Through long time scale coarse-grained and atomic simulations, we have found that the APP TMD can bind to the catalytic subunit presenilin 1 (PS1) on an extended surface covering PS1’s TMD2/6/9 and PAL motif that are all known to be essential for enzymatic activity. This initial substrate binding could lead to reduction in the vertical gap between APP’s ε-cleavage sites and γ-secretase’s active center, enhanced flexibility and hydration levels around the ε-sites, and the presentation of these sites to the enzyme. There are heterogeneous substrate binding poses in which the substrate is found to bind to either the N- or C-terminal parts of PS1, or both. Moreover, we also find that the stability of the binding poses can be modulated by the flexibility of substrate TMD. Especially, the APP substrate, when deprived of bending fluctuation, does not bind to TMD9 at PS1’s C-terminus. Our simulations have revealed further that another substrate of γ-secretase, namely, notch receptors, though bearing a rigid TMD, can still bind to PS1 TMD9, but by a different mechanism, suggesting that the influence of substrate flexibility is context-dependent. Together, these findings shed light on the mechanism of initial substrate docking of γ-secretase and the role of substrate flexibility in this process