5,305 research outputs found

    A new perspective on the analysis of helix-helix packing preferences in globular proteins

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    For many years it had been believed that steric compatibility of helix interfaces could be the source of the observed preference for particular angles between neighbouring helices as emerging from statistical analysis of protein databanks. Several elegant models describing how side chains on helices can interdigitate without steric clashes were able to account quite reasonably for the observed distributions. However, it was later recognized (Bowie, 1997 and Walther, 1998) that the ``bare'' measured angle distribution should be corrected to avoid statistical bias. Disappointingly, the rescaled distributions dramatically lost their similarity with theoretical predictions casting many doubts on the validity of the geometrical assumptions and models. In this report we elucidate a few points concerning the proper choice of the random reference distribution. In particular we show the existence of crucial corrections due to the correct implementation of the approach used to discriminate whether two helices are in contact or not and to measure their relative orientations. By using this new rescaling, the ``true'' packing angle preferences are well described, even more than with the original ``bare'' distribution, by regular packing models.Comment: 23 pages, 5 figure

    Simple solvation potential for coarse-grained models of proteins

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    We formulate a simple solvation potential based on a coarsed-grain representation of amino acids with two spheres modeling the CαC_\alpha atom and an effective side-chain centroid. The potential relies on a new method for estimating the buried area of residues, based on counting the effective number of burying neighbours in a suitable way. This latter quantity shows a good correlation with the buried area of residues computed from all atom crystallographic structures. We check the discriminatory power of the solvation potential alone to identify the native fold of a protein from a set of decoys and show the potential to be considerably selective.Comment: 18 pages, 8 tables, 3 figure

    Value of thermostatic loads in future low-carbon Great Britain system

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    This paper quantifies the value of a large population of heterogeneous thermostatically controlled loads (TCLs). The TCL dynamics are regulated by means of an advanced demand side response model (DSRM). It optimally determines the flexible energy/power consumption and simultaneously allocates multiple ancillary services. This model explicitly incorporates the control of dynamics of the TCL recovery pattern after the provision of the selected services. The proposed framework is integrated in a mixed integer linear programming formulation for a multi-stage stochastic unit commitment. The scheduling routine considers inertia-dependent frequency response requirements to deal with the drastic reduction of system inertia under future low-carbon scenarios. Case studies focus on the system operation cost and CO2 emissions reductions for individual TCLs for a) different future network scenarios, b) different frequency requirements, c) changes of TCL parameters (e.g. coefficient of performance, thermal insulation etc.)

    Promoting Tissue Repair by Micrograft Stem Cells Delivery

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    Stochastic scheduling with inertia-dependent fast frequency response requirements

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    High penetration of wind generation will increase the requirement for fast frequency response services as currently wind plants do not provide inertial response. Although the importance of inertia reduction has been widely recognized, its impact on the system scheduling has not been fully investigated. In this context, this paper proposes a novel mixed integer linear programming (MILP) formulation for stochastic unit commitment that optimizes system operation by simultaneously scheduling energy production, standing/spinning reserves and inertia-dependent fast frequency response in light of uncertainties associated with wind production and generation outages. Post-fault dynamic frequency requirements, rate of change of frequency, frequency nadir and quasi-steady-state frequency are formulated as MILP constraints by using the simplified model of system dynamics. Moreover the proposed methodology enables the impact of wind uncertainty on system inertia to be considered. Case studies are carried out on the 2030 Great Britain system to demonstrate the importance of incorporating inertia-dependent fast frequency response in the stochastic scheduling and to indicate the potential for the proposed model to inform reviews of grid codes associated with fast frequency response and future development of inertia-related market

    Folding Rate Optimization Promotes Frustrated Interactions in Entangled Protein Structures

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    Many native structures of proteins accomodate complex topological motifs such as knots, lassos, and other geometrical entanglements. How proteins can fold quickly even in the presence of such topological obstacles is a debated question in structural biology. Recently, the hypothesis that energetic frustration might be a mechanism to avoid topological frustration has been put forward based on the empirical observation that loops involved in entanglements are stabilized by weak interactions between amino-acids at their extrema. To verify this idea, we use a toy lattice model for the folding of proteins into two almost identical structures, one entangled and one not. As expected, the folding time is longer when random sequences folds into the entangled structure. This holds also under an evolutionary pressure simulated by optimizing the folding time. It turns out that optmized protein sequences in the entangled structure are in fact characterized by frustrated interactions at the closures of entangled loops. This phenomenon is much less enhanced in the control case where the entanglement is not present. Our findings, which are in agreement with experimental observations, corroborate the idea that an evolutionary pressure shapes the folding funnel to avoid topological and kinetic traps

    Continuum model for polymers with finite thickness

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    We consider the continuum limit of a recently-introduced model for discretized thick polymers, or tubes. We address both analytically and numerically how the polymer thickness influences the decay of tangent-tangent correlations and find how the persistence length scales with the thickness and the torsional rigidity of the tube centerline. At variance with the worm-like chain model, the phase diagram that we obtain for a continuous tube is richer; in particular, for a given polymer thickness there exists a threshold value for the centerline torsional rigidity separating a simple exponential decay of the tangent-tangent correlation from an oscillatory one.Comment: 8 pages, 4 figures. Accepted for publication in J. Phys.

    Lipids in liver failure syndromes: a focus on eicosanoids, specialized pro-resolvinglipid mediators and lysophospholipids.

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    Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described

    Sequence and structural patterns detected in entangled proteins reveal the importance of co-translational folding

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    Proteins must fold quickly to acquire their biologically functional three-dimensional native structures. Hence, these are mainly stabilized by local contacts, while intricate topologies such as knots are rare. Here, we reveal the existence of specific patterns adopted by protein sequences and structures to deal with backbone self-entanglement. A large scale analysis of the Protein Data Bank shows that loops significantly intertwined with another chain portion are typically closed by weakly bound amino acids. Why is this energetic frustration maintained? A possible picture is that entangled loops are formed only toward the end of the folding process to avoid kinetic traps. Consistently, these loops are more frequently found to be wrapped around a portion of the chain on their N-terminal side, the one translated earlier at the ribosome. Finally, these motifs are less abundant in natural native states than in simulated protein-like structures, yet they appear in 32% of proteins, which in some cases display an amazingly complex intertwining

    An efficient algorithm to perform local concerted movements of a chain molecule

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    The devising of efficient concerted rotation moves that modify only selected local portions of chain molecules is a long studied problem. Possible applications range from speeding the uncorrelated sampling of polymeric dense systems to loop reconstruction and structure refinement in protein modeling. Here, we propose and validate, on a few pedagogical examples, a novel numerical strategy that generalizes the notion of concerted rotation. The usage of the Denavit-Hartenberg parameters for chain description allows all possible choices for the subset of degrees of freedom to be modified in the move. They can be arbitrarily distributed along the chain and can be distanced between consecutive monomers as well. The efficiency of the methodology capitalizes on the inherent geometrical structure of the manifold defined by all chain configurations compatible with the fixed degrees of freedom. The chain portion to be moved is first opened along a direction chosen in the tangent space to the manifold, and then closed in the orthogonal space. As a consequence, in Monte Carlo simulations detailed balance is easily enforced without the need of using Jacobian reweighting. Moreover, the relative fluctuations of the degrees of freedom involved in the move can be easily tuned. We show different applications: the manifold of possible configurations is explored in a very efficient way for a protein fragment and for a cyclic molecule; the "local backbone volume", related to the volume spanned by the manifold, reproduces the mobility profile of all-α helical proteins; the refinement of small protein fragments with different secondary structures is addressed. The presented results suggest our methodology as a valuable exploration and sampling tool in the context of bio-molecular simulations
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