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"Models, Molecular."
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Statistical modelling of molecular descriptors in QSAR/QSPR
This handbook and ready reference presents a combination of statistical, information-theoretic, and data analysis methods to meet the challenge of designing empirical models involving molecular descriptors within bioinformatics.
eBook
Shared structural mechanisms of general anaesthetics and benzodiazepines
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA
A
) receptors to dampen neuronal activity in the brain
1
–
5
. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA
A
receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA
A
receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA
A
receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
Cryo-electron microscopy structures of GABA
A
receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.
Journal Article
Critical population and error threshold on the sharp peak landscape for a Moran model
The goal of this work is to propose a finite population counterpart to Eigen's model, which incorporates stochastic effects. The author considers a Moran model describing the evolution of a population of size m of chromosomes of length \\ell over an alphabet of cardinality \\kappa. The mutation probability per locus is q. He deals only with the sharp peak landscape: the replication rate is \\sigma>1 for the master sequence and 1 for the other sequences. He studies the equilibrium distribution of the process in the regime where \\ell\\to +\\infty,\\qquad m\\to +\\infty,\\qquad q\\to 0, {\\ell q} \\to a\\in ]0,+\\infty[, \\qquad\\frac{m}{\\ell}\\to\\alpha\\in [0,+\\infty].
eBook
Clogging transition of many-particle systems flowing through bottlenecks
When a large set of discrete bodies passes through a bottleneck, the flow may become intermittent due to the development of clogs that obstruct the constriction. Clogging is observed, for instance, in colloidal suspensions, granular materials and crowd swarming, where consequences may be dramatic. Despite its ubiquity, a general framework embracing research in such a wide variety of scenarios is still lacking. We show that in systems of very different nature and scale -including sheep herds, pedestrian crowds, assemblies of grains and colloids- the probability distribution of time lapses between the passages of consecutive bodies exhibits a power-law tail with an exponent that depends on the system condition. Consequently, we identify the transition to clogging in terms of the divergence of the average time lapse. Such a unified description allows us to put forward a qualitative clogging state diagram whose most conspicuous feature is the presence of a length scale qualitatively related to the presence of a finite size orifice. This approach helps to understand paradoxical phenomena, such as the faster-is-slower effect predicted for pedestrians evacuating a room and might become a starting point for researchers working in a wide variety of situations where clogging represents a hindrance.
Journal Article
Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2
The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart.
Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.
Journal Article
New metastable form of ice and its role in the homogeneous crystallization of water
The homogeneous crystallization of water at low temperature is believed to occur through the direct nucleation of cubic (I
c
) and hexagonal (I
h
) ices. Here, we provide evidence from molecular simulations that the nucleation of ice proceeds through the formation of a new metastable phase, which we name Ice 0. We find that Ice 0 is structurally similar to the supercooled liquid, and that on growth it gradually converts into a stacking of Ice I
c
and I
h
. We suggest that this mechanism provides a thermodynamic explanation for the location and pressure dependence of the homogeneous nucleation temperature, and that Ice 0 controls the homogeneous nucleation of low-pressure ices, acting as a precursor to crystallization in accordance with Ostwald’s step rule of phases. Our findings show that metastable crystalline phases of water may play roles that have been largely overlooked.
At sufficiently low temperature, liquid water crystallizes into ices with cubic or hexagonal symmetry. A simulation study now shows that the nucleation of water into atomic stackings of cubic and hexagonal ices occurs through a metastable precursor phase with tetragonal symmetry, and that this scenario provides an explanation for the unusual pressure dependence of water’s homogeneous crystal-nucleation temperature.
Journal Article
Molecular basis for amyloid-β polymorphism
Amyloid-beta (Aβ) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer’s disease. Aβ molecules form β-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of Aβ has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate Aβ polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of Aβ. These structures, all of short, self-complementing pairs of β-sheets termed steric zippers, reveal a variety of modes of self-association of Aβ. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to Aβ. These structures and molecular models contribute fundamental information for understanding Aβ polymorphic nature and pathogenesis.
Journal Article
Molecular basis for insulin fibril assembly
In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-β spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 Å resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated β-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.
Journal Article
A Small-Molecule Screen Identifies L-Kynurenine as a Competitive Inhibitor of TAA1/TAR Activity in Ethylene-Directed Auxin Biosynthesis and Root Growth in Arabidopsis
The interactions between phytohormones are crucial for plants to adapt to complex environmental changes. One example is the ethylene-regulated local auxin biosynthesis in roots, which partly contributes to ethylene-directed root development and gravitropism. Using a chemical biology approach, we identified a small molecule, L-kynurenine (Kyn), which effectively inhibited ethylene responses in Arabidopsis thaliana root tissues. Kyn application repressed nuclear accumulation of the ETHYLENE INSENSITIVE3 (EIN3) transcription factor. Moreover, Kyn application decreased ethylene-induced auxin biosynthesis in roots, and TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS1/TRYPTOPHAN AMINOTRANSFERASE RELATEDs (TAA1/TARs), the key enzymes in the indole-3-pyruvic acid pathway of auxin biosynthesis, were identified as the molecular targets of Kyn. Further biochemical and phenotypic analyses revealed that Kyn, being an alternate substrate, competitively inhibits TAA1/TAR activity, and Kyn treatment mimicked the loss of TAA1/TAR functions. Molecular modeling and sequence alignments suggested that Kyn effectively and selectively binds to the substrate pocket of TAA1/TAR proteins but not those of other families of aminotransferases. To elucidate the destabilizing effect of Kyn on EIN3, we further found that auxin enhanced EIN3 nuclear accumulation in an EIN3 BINDING F-BOX PROTEIN1 (EBF1)/EBF2-dependent manner, suggesting the existence of a positive feedback loop between auxin biosynthesis and ethylene signaling. Thus, our study not only reveals a new level of interactions between ethylene and auxin pathways but also offers an efficient method to explore and exploit TAA1/TAR-dependent auxin biosynthesis.
Journal Article