1,721,016 research outputs found
The development of a coarse-grain biomembrane model and its use in multiscale simulations of solute permeability
No full textA new simplified particle-based computer model for hydrated phosphohpid bilayers is presented. In the model, each lipid molecule, in reality comprising more than one hundrec atoms, is reduced to a collection of ten "'coarse-grain'' macrounits. Compared with available arse-grain methods, three novel aspects are introduced. First, electrostatics are explicitly incorporated via charges and dipoles. Second, water is accurately (yet efficiently) described, on an individual level, by the soft sticky dipole model. Third, hydrocarbon tails are modelled using the anisotropic Gay-Berne potential. Simulations are conducted by rigid body molecular dynamics, using software specifically designed and implemented for this project.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Physical properties of mixed bilayers containing lamellar and nonlamellar lipids: insights from coarse-grain molecular dynamics simulations
No full textA recently developed coarse-grain model is applied to simulate hydrated membranes containing the lamellar lipid DOPC and the nonlamellar lipid DOPE. In a first series of simulations, DOPC–water and DOPE–water systems are shown to form respectively bilayers and inverse hexagonal phases, in agreement with the well-known behaviour observed experimentally. A second set of calculations is then run to investigate several fundamental physical features of mixed DOPC–DOPE bilayers at different relative compositions. In particular, a quantitative characterisation is obtained of the internal distributions (profiles) of lateral pressure and electrical potential. These two properties, very difficult to measure experimentally, are thought to underpin many key membrane phenomena, including nonspecific lipid-mediated mechanisms of protein regulation. The molecular origin of the distributions, and their dependence on changes in the DOPC : DOPE ratio, are explained through an analysis of separate contributions from individual interaction types and molecular groups
Coarse-grain modelling of DMPC and DOPC lipid bilayers
No full textOur recently developed coarse-grain model for dimyristoylphosphatidylcholine (DMPC) has been improved and extended to dioleylphosphatidylcholine (DOPC), a more typical constituent of real biological membranes. Single-component DMPC and DOPC bilayers have been simulated using microsecond-long molecular dynamics. We investigated properties that are difficult or impossible to access experimentally, such as the pressure distribution, the spontaneous curvature and the diffusion pattern of individual lipid molecules. Moreover, we studied the dipole potential, a basic physical feature of paramount biological importance that cannot be currently modelled by other coarse-grain approaches. In fact, a complete representation of the system electrostatics and a realistic description of the water component make our method unique amongst the existing coarse-grain membrane models. The spontaneous permeation of water, a phenomenon out of reach of standard atomistic models, was also observed and quantified; this was possible thanks to the efficiency of our model, which is about two orders of magnitude less computationally expensive than atomic-level counterparts. Results are generally in good agreement with the literature data. Further model extensions and future applications are proposed
Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics
No full textThe unassisted permeation process of ?-blocker drugs (alprenolol, atenolol, pindolol) and steroid hormones (progesterone, testosterone) through a lipid membrane is simulated by a novel dual-resolution molecular dynamics approach. The lipid and water molecules are described by simple and efficient coarse-grain models, whereas the drug and hormone permeants are represented by traditional atomistic models. Our hybrid method is about two orders of magnitude faster than standard atomic-level counterparts. For each permeant, we calculate the transfer free energy as a function of depth inside the bilayer; these data indicate the location across the membrane where the solutes preferentially partition. Using the free energy profiles, we develop a simple expression that proves remarkably accurate in predicting experimental permeability rankings; the proposed permeation model highlights and addresses potentially problematic aspects of the standard solubility-diffusion theory. We also calculate the diffusion coefficients of the permeants, and track their lateral motion to study their diffusive patterns. Furthermore, we show the drugs' perturbing effect on the bilayer structure and quantify the steroids' preferred orientations. The results obtained compare favourably with experimental measurements and traditional atomic-level simulation data reported in the literature. Promising potential applications of our methodology to areas such as drug design and membrane-protein modelling are discusse
The ELBA force field for coarse-grain modeling of lipid membranes
No full textA new coarse-grain model for molecular dynamics simulation of lipid membranes is presented. Following a simple and conventional approach, lipid molecules are modeled by spherical sites, each representing a group of several atoms. In contrast to common coarse-grain methods, two original (interdependent) features are here adopted. First, the main electrostatics are modeled explicitly by charges and dipoles, which interact realistically through a relative dielectric constant of unity (?r=1). Second, water molecules are represented individually through a new parametrization of the simple Stockmayer potential for polar fluids; each water molecule is therefore described by a single spherical site embedded with a point dipole. The force field is shown to accurately reproduce the main physical properties of single-species phospholipid bilayers comprising dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) in the liquid crystal phase, as well as distearoylphosphatidylcholine (DSPC) in the liquid crystal and gel phases. Insights are presented into fundamental properties and phenomena that can be difficult or impossible to study with alternative computational or experimental methods. For example, we investigate the internal pressure distribution, dipole potential, lipid diffusion, and spontaneous self-assembly. Simulations lasting up to 1.5 microseconds were conducted for systems of different sizes (128, 512 and 1058 lipids); this also allowed us to identify size-dependent artifacts that are expected to affect membrane simulations in general. Future extensions and applications are discussed, particularly in relation to the methodology's inherent multiscale capabilities
Permeability of small molecules through a lipid bilayer: a multiscale simulation study
No full textThe transmembrane permeation of eight small (molecular weight <100) organic molecules across a phospholipid bilayer is investigated by multiscale molecular dynamics simulation. The bilayer and hydrating water are represented by simplified, efficient coarse-grain models, whereas the permeating molecules are described by a standard atomic-level force-field. Permeability properties are obtained through a refined version of the z-constraint algorithm. By constraining each permeant at selected depths inside the bilayer, we have sampled free energy differences and diffusion coefficients across the membrane. These data have been combined, according to the inhomogeneous solubility?diffusion model, to yield the permeability coefficients. The results are generally consistent with previous atomic-level calculations and available experimental data. Computationally, our multiscale approach proves 2 orders of magnitude faster than traditional atomic-level methods
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
Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes
No full textTriclocarban and triclosan, two potent antibacterial molecules present in many consumer products, have been subject to growing debate on a number of issues, particularly in relation to their possible role in causing microbial resistance. In this computational study, we present molecular-level insights into the interaction between these antimicrobial agents and hydrated phospholipid bilayers (taken as a simple model for the cell membrane). Simulations are conducted by a novel ‘dual-resolution’ molecular dynamics approach which combines accuracy with efficiency: the antimicrobials, modelled atomistically, are mixed with simplified (coarse-grain) models of lipids and water. A first set of calculations is run to study the antimicrobials' transfer free energies and orientations as a function of depth inside the membrane. Both molecules are predicted to preferentially accumulate in the lipid headgroup–glycerol region; this finding, which reproduces corresponding experimental data, is also discussed in terms of a general relation between solute partitioning and the intramembrane distribution of pressure. A second set of runs involves membranes incorporated with different molar concentrations of antimicrobial molecules (up to one antimicrobial per two lipids). We study the effects induced on fundamental membrane properties, such as the electron density, lateral pressure and electrical potential profiles. In particular, the analysis of the spontaneous curvature indicates that increasing antimicrobial concentrations promote a ‘destabilizing’ tendency towards non-bilayer phases, as observed experimentally. The antimicrobials' influence on the self-assembly process is also investigated. The significance of our results in the context of current theories of antimicrobial action is discussed. <br/
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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