1,720,974 research outputs found
Coarse-Grained Description of Protein Internal Dynamics: An Optimal Strategy for Decomposing Proteins in Rigid Subunits
No full textAbstractThe possibility of accurately describing the internal dynamics of proteins, in terms of movements of a few approximately-rigid subparts, is an appealing biophysical problem with important implications for the analysis and interpretation of data from experiments or numerical simulations. The problem is tackled here by means of a novel variational approach that exploits information about equilibrium fluctuations of interresidues distances, provided, e.g., by atomistic molecular dynamics simulations or coarse-grained models. No contiguity in primary sequence or in space is enforced a priori for amino acids grouped in the same rigid unit. The identification of the rigid protein moduli, or dynamical domains, provides valuable insight into functionally oriented aspects of protein internal dynamics. To illustrate this point, we first discuss the decomposition of adenylate kinase and HIV-1 protease and then extend the investigation to several representatives of the hydrolase enzymatic class. The known catalytic site of these enzymes is found to be preferentially located close to the boundary separating the two primary dynamical subdomains
Small- and Large-Scale Conformational Changes of Adenylate Kinase: A Molecular Dynamics Study of the Subdomain Motion and Mechanics
No full textAbstractAdenylate kinase, an enzyme that catalyzes the phosphoryl transfer between ATP and AMP, can interconvert between the open and catalytically potent (closed) forms even without binding ligands. Several aspects of the enzyme elasticity and internal dynamics are analyzed here by atomistic molecular dynamics simulations covering a total time span of 100ns. This duration is sufficiently long to reveal a partial conversion of the enzyme that proceeds through jumps between structurally different substates. The intra- and intersubstates contributions to the enzyme's structural fluctuations are analyzed and compared both in magnitude and directionality. It is found that, despite the structural heterogeneity of the visited conformers, the generalized directions accounting for conformational fluctuations within and across the substates are mutually consistent and can be described by a limited set of collective modes. The functional-oriented nature of the consensus modes is suggested by their good overlap with the deformation vector bridging the open and closed crystal structures. The consistency of adenylate kinase's internal dynamics over timescales wide enough to capture intra- and intersubstates fluctuations adds elements in favor of the recent proposal that the free (apo) enzyme possesses an innate ability to sustain the open/close conformational changes
Verification of Programs with Exceptions Through Operator Precedence Automata
Full text linkOperator Precedence Languages are one of the most expressive classes of context-free languages that enable Model Checking. Recently, the First-Order complete Precedence Oriented Temporal Logic (POTL) has been introduced for expressing properties on models defined through Operator Precedence Automata (OPA), a variant of Pushdown Automata for OPLs; moreover, an efficient tool called Precedence Oriented Model Checker (POMC) was devised for POTL. We propose here the core algorithms of POMC for on-the-fly depth-first exploration of the search space: for OPA, a reachability algorithm; for their ω -word variant, a fair-cycle detection algorithm. We have refined the tool with a user-friendly DSL called MiniProc for expressing procedural code with exceptions. We show how the expressiveness of POMC can be used to verify programs which make use of exceptions, thus overcoming the limits of LTL-based Model Checking. We demonstrate the effectiveness of POMC through a case study
Structural and dynamical alignment of enzymes with partial structural similarity
No full textProteins and enzymes, in order to carry our their biological tasks, often need to sustain concerted displacements of a large number of amino acids. In recent years many theoretical and computational studies have pointed out how these large scale movements, also termed slow modes or essential dynamical spaces, are mostly dictated by the overall structural organization of the protein. Several fundamental questions arise when this fact is complemented by the observation that enzymes within the same enzymatic superfamily can have remarkable conformational differences. Could their large scale movements be similar despite the difference in structure? In this study we address this issue and present a quantitative scheme for comparing the slow modes in proteins that, though differing in sequence, length and tertiary structure, still admit a partial structural superposition. We illustrate the application of the method to two representatives of the protease enzymatic superfamily, carboxypeptidase A and pyroglutamyl peptidase
Bridging the Atomic and Coarse-Grained Descriptions of Collective Motions in Proteins
No full textProtein structures are carefully "designed" to balance the need of thermodynamical stability with the necessity of sustaining conformational changes and efficiently interconverting among different functionally relevant conformers. This subtle equilibrium reverberates in the complexity of the free-energy landscape which is endowed by a variety of local minima of varying depth and breadth corresponding to the salient structural states of the molecules. In this chapter we will present some concepts and computational algorithms that can be used to characterize the internal dynamics of proteins and relate it to their "functional mechanics". We will apply these concepts to the analysis of a molecular dynamics simulation of adenylate kinase, a protein for which the structural rearrangement is known to be crucial for the accomplishment of its biological function. We will show how, despite the structural heterogeneity of the explored conformational ensemble, the generalized directions accounting for conformational fluctuations within and across the visited conformational substates are robust and can be described by a limited set of collective coordinates. Finally, as a term of comparison, we will show that in the case of HIV-1 Transactivator of Transcription (TAT), a naturally unstructured protein, the lack of any hierarchical organization of the free-energy minima results in a poor consistency of the essential dynamical spaces sampled during the dynamical evolution of the system
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
ALADYN: a web server for aligning proteins by matching their large-scale motion
No full textThe ALADYN web server aligns pairs of protein structures by comparing their internal dynamics and detecting regions that sustain similar large-scale movements. The latter often accompany functional conformational changes in proteins and enzymes. The ALADYN dynamics-based alignment can therefore highlight functionally-oriented correspondences that could be more elusive to sequence- or structure-based comparisons. The ALADYN server takes the structure files of the two proteins as input. The optimal relative positioning of the molecules is found by maximizing the similarity of the pattern of structural fluctuations which are calculated via an elastic network model. The resulting alignment is presented via an interactive graphical Java applet and is accompanied by a number of quantitative indicators and downloadable data files. The ALADYN web server is freely accessible at the http://aladyn.escience-lab.org address
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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