1,720,995 research outputs found
Coarse-grained simulation of dynamin-mediated fission
No full textFission is a process in which a region of a lipid bilayer is deformed and separated from its host membrane, so that an additional, topologically independent compartment surrounded by a continuous lipid bilayer is formed. It is a fundamental process in the organization of the compartmentalization of living organisms and carefully regulated by a number of membrane-shaping proteins. An important group within these is the dynamin family of proteins that are involved in the final severance of the hourglass-shaped neck, via which the growing compartment remains connected to the main volume until the completion of fission. We present computer simulations testing different hypotheses of how dynamin proteins facilitate fission by constriction and curvature. Our results on constraint-induced fission of cylindrical membrane tubes emphasize the importance of the local creation of positive curvature and reveal a complex picture of fission, in which the topological transformation can become arrested in an intermediate stage if the proteins constituting the fission machinery are not adaptive
Mechanisms of Vesicle Spreading on Surfaces: Coarse-Grained Simulations
No full textExposition of unilamellar vesicles to attractive surfaces is a frequently used way to create supported lipid bilayers. Although this approach is known to produce continuous supported bilayer coatings, the mechanism of their formation and its dependence on factors like surface interaction and roughness or membrane tension as well as the interplay between neighboring vesicles or the involvement of preadsorbed bilayer patches are not well understood. Using dissipative particle dynamics simulations, we assess different mechanisms of vesicle spreading on attractive surfaces, placing special emphasis on the orientation of the resulting bilayer. Making use of the universality of collective phenomena in lipid membranes, we employed a solvent-free coarse-grained model, enabling us to cover the relatively large system sizes and time scales required. Our results indicate that one can control the mechanism of vesicle spreading by tuning the strength and range of the interactions with the substrate as well as the surface's roughness, resulting in a switch from a predominant inside-up to an outside-up orientation of the created supported bilayer.Volkswagen Foundation; DFG [SFB 803/B3
Mechanics of membrane fusion/pore formation
No full textLipid bilayers play a fundamental role in many biological processes, and a considerable effort has been invested in understanding their behavior and the mechanism of topological changes like fusion and pore formation. Due to the time- and length-scale on which these processes occur, computational methods have proven to be an especially useful tool in their study. With their help, a number of interesting findings about the shape of fusion intermediates could be obtained, and novel hypotheses about the mechanism of topological changes and the involvement of peptides therein were suggested. In this work, we try to present a summary of these developments together with some hitherto unpublished results, featuring, among others, the shape of stalks and fusion pores, possible modes of action of the influenza HA fusion peptide and the SNARE protein complex, the mechanism of supported lipid bilayer formation by vesicle spreading, and the free energy and transition pathway of the fusion process. (C) 2014 Elsevier Ireland Ltd. All rights reserved
Molecular View of the Role of Fusion Peptides in Promoting Positive Membrane Curvature
Get PDFFusion peptides are moderately hydrophobic segments of viral and nonviral membrane fusion proteins that enable these proteins to fuse two closely apposed biological membranes. In vitro assays furthermore show that even isolated fusion peptides alone can support membrane fusion in model systems. In addition, the fusion peptides have a distinct effect on the phase diagram of lipid mixtures. Here, we present molecular dynamics simulations investigating the effect of a particular fusion peptide, the influenza hemagglutinin fusion peptide and some of its mutants, on the lipid phase diagram. We detect a systematic shift toward phases with more positive mean curvature in the presence of the peptides, as well as an occurrence of bicontinuous cubic phases, which indicates a stabilization of Gaussian curvature. The wild-type fusion peptide has a stronger effect on the phase behavior as compared to the mutants, which we relate to its boomerang shape. Our results point to a different role of fusion peptides than hitherto assumed, the stabilization of pores rather than stalks along the fusion pathway.
Transition Path from Two Apposed Membranes to a Stalk Obtained by a Combination of Particle Simulations and String Method
No full textThe formation of an hourglass-shaped passage (stalk) connecting two apposed membranes is an essential initial step in membrane fusion. The most probable transition path from two separate membranes to a stalk, i.e., the minimum free-energy path (MFEP), is constructed using a combination of particle simulations and string method. For the reversible transition path in the coarse-grained membrane model, a collective order parameter, m, can be identified as the local difference of hydrophilic and hydrophobic densities. In particle simulations, the free energy F[m] as a functional of m is not readily available. This difficulty is overcome by an equation-free approach, where the morphology and the excess free energy along the MFEP are obtained by an on-the-fly string method. The transition state is confirmed by diagonalization of order-parameter fluctuations and by the probability of reaching either stalk or bilayer morphology from different positions along the MFEP.NSERC; [SFB 803]; [SFB 602
Of Stalks and Diamonds. Simulation Studies of Membrane Fusion and the Role of Fusion Peptides
Get PDFMixtures of lipids and water form lyotropic phases in which the polar and apolar moieties are separated by an interface lined with the headgroups of the lipid molecules. These phases are fluid-like in the sense that they are very flexible and that the individual lipids possess a high mobility. At the same time, however, their overall shape is relatively stable. This behavior is the basis of all cellular
life and a considerable part of biology revolves around the organization of lipid aggregates into membranes surrounding cells and cellular compartments. A complex machinery of proteins and peptides is involved in controlling the fusion and fission of these membranes as well as the transport through them.
This thesis presents insights obtained from computer simulations, taking a closer look at the intermediate stages of membrane fusion and the role of fusion peptides. In particular, molecular dynamics simulations of vesicle fusion are presented, giving evidence for an alternative fusion pathway. In addition, the effects of the Influenza HA fusion peptide on stalk formation and the phase diagram of representative mixtures of lipids and water are studied placing
special emphasis on the curvature of the lipid/water interface. A method to analyze the morphology of molecular aggregates using morphological image analysis is presented as well. Finally, the effects of introducing bundling, i.e. relative restraints on groups of molecules, to the SPC water model has been investigated. Bundling is required for the simultaneous representation of water at the fine- and coarse-grained level in multiscale simulations.
Free-energy calculation methods for collective phenomena in membranes
No full textCollective phenomena in membranes are those which involve the co-operative reorganization of many molecules. Examples of these are membrane fusion, pore formation, bending, adhesion or fission. The time and length scales, on which these processes occur, pose a challenge for atomistic simulations. Therefore, in order to solve the length scale problem it is popular to introduce a coarse-grained representation. To facilitate sampling of the relevant states additional computational techniques, which encourage the system to explore the free-energy landscape far from equilibrium and visit transition states, are needed. These computational techniques provide insights about the free-energy changes involved in collective transformations of membranes, yielding information about the rate limiting states, the transformation mechanism and the influence of architectural, compositional and interaction parameters. A common approach is to identify an order parameter (or reaction coordinate), which characterizes the pathway of membrane reorganization. However, no general strategy exists to define such an order parameter that can properly describe cooperative reorganizations in membranes. Recently developed methods can overcome this problem of the orderparameter choice and allow us to study collective phenomena in membranes. We will discuss such methods as thermodynamic integration, umbrella sampling, and the string method and results provided by their applications to particle-based simulations, particularly focusing on membrane fusion and pore formation.Julich Supercomputer Center; GWDG Gottingen; [SFB 803
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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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