1,721,012 research outputs found
A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1
No full textWe introduce a new class of collective variables which allow forming efficiently beta-sheet structures in all-atom explicit-solvent simulations of proteins. By this approach we are able to systematically fold a 16-residue beta hairpin using metadynamics on a single replica. Application to the 56-residue SH3 and GB1 proteins show that, starting from extended states, in ∼100 ns tens of structures containing more than 30% beta-sheet are obtained, including parts of the native fold. Using these variables may allow folding moderate size proteins with an accurate explicit solvent description. Moreover, it may allow investigating the presence of misfolded states that are relevant for diseases (e.g., prion and Alzheimer) and studying beta-aggregation (amyloid diseases)
Optimizing the performance of bias-exchange metadynamics: Folding a 48-residue LysM domain using a coarse-grained model
No full textMETAGUI. A VMD interface for analyzing metadynamics and molecular dynamics simulations
No full textWe present a new computational tool, METAGUI, which extends the VMD program with a graphical user interface that allows constructing a thermodynamic and kinetic model of a given process simulated by large-scale molecular dynamics. The tool is specially designed for analyzing metadynamics based simulations. The huge amount of diverse structures generated during such a simulation is partitioned into a set of microstates (i.e. structures with similar values of the collective variables). Their relative free energies are then computed by a weighted-histogram procedure and the most relevant free energy wells are identified by diagonalization of the rate matrix followed by a commitor analysis. All this procedure leads to a convenient representation of the metastable states and long-time kinetics of the system which can be compared with experimental data. The tool allows to seamlessly switch between a collective variables space representation of microstates and their atomic structure representation, which greatly facilitates the set-up and analysis of molecular dynamics simulations. METAGUI is based on the output format of the PLUMED plugin, making it compatible with a number of different molecular dynamics packages like AMBER, NAMD, GROMACS and several others. The METAGUI source files can be downloaded from the PLUMED web site (http://www.plumed-code.org). RI Pietrucci, Fabio/C-2326-200
Substrate Binding Mechanism of HIV-1 Protease from Explicit-Solvent Atomistic Simulations
No full textThe binding mechanism of a peptide substrate (Thr-Ile-Met-Met-Gln-Arg, cleavage site p2-NC of the viral polyprotein) to wild-type HIV-1 protease has been investigated by 1.6 μs biased all-atom molecular dynamics simulations in explicit water. The configuration space has been explored biasing seven reaction coordinates by the bias-exchange metadynamics technique. The structure of the Michaelis complex is obtained starting from the substrate outside the enzyme within a backbone rmsd of 0.9 Å. The calculated free energy of binding is −6 kcal/mol, and the kinetic constants for association and dissociation are 1.3 × 106 M−1 s−1 and 57 s−1, respectively, consistent with experiments. In the main binding pathway, the flaps of the protease do not open sizably. The substrate slides inside the enzyme cavity from the tight lateral channel. This may contrast with the natural polyprotein substrate which is expected to bind by opening the flaps. Thus, mutations might influence differently the binding kinetics of peptidomimetic ligands and of the natural substrate
Vacancy-vacancy interaction and oxygen diffusion in stabilized cubic ZrO2 from first principles
No full textBased on ab initio and classical molecular-dynamics simulations, we investigate the role of vacancy-vacancy interaction in oxygen conductivity of yttria-stabilized and scandia-stabilized cubic zirconia. It turns out that a sizable fraction of possible configurations of vacancies are local unstable, although the vacancies are at least third nearest neighbors each other. Investigation of oxygen migration pathways by ab initio metadynamics simulations show the occurrence of multiple-vacancy concerted jumps in correspondence of an unstable arrival state for a single vacancy jump. Furthermore, in the case of single vacancy jump, we have observed a strong dependence of the activation barrier on the position of the other vacancies, similar in strength to the dependence of the activation energy on the presence of nearest-neighbors yttrium ions, customarily assumed to constitute a blocking site for vacancy migration. Our results point to the need of improving existing models for oxygen diffusion in stabilized zirconia by including vacancy-vacancy interactions
Nucleation process of a fibril precursor in the C-terminal segment of amyloid-beta
No full textBy extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-β, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent" fibril may differ from the one of an "extended" fibril. © 2013 American Physical Society
Multidimensional View of Amyloid Fibril Nucleation in Atomistic Detail
No full textStarting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 polyvaline chains in explicit solvent, employing molecular dynamics accelerated by bias-exchange metadynamics. We exploited 8 different collective variables to compute the free energy of hundreds of putative aggregate structures, with variable content of parallel and antiparallel beta-sheets and different packing among the sheets. This allowed characterizing in detail a possible nucleation pathway for the formation of amyloid fibrils: first the system forms a relatively large ordered nucleus of antiparallel beta-sheets, and then a few parallel sheets start appearing. The relevant nucleation process culminates at this point: when a sufficient number of parallel sheets is formed, the free energy starts to decrease toward a new minimum in which this structure is predominant. The complex nucleation pathway we found cannot be described within classical nucleation theory, namely employing a unique simple reaction coordinate like the total content of beta-sheets. © 2012 American Chemical Society
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
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
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