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Molecular dynamics simulations of monomeric apolipoprotein A-I from a recent X-ray structure
No full textWe have examined the X-ray crystal structure recently refined by Ajees and colleagues (Ajees et al. 2006) for monomeric apolipoprotein A-I (apoA-I). Because the structure, which has been crystallized together with chromium organic compounds, possesses a substantially higher percentage of alpha helicity than is generally estimated experimentally for the lipid-free monomeric apoA-I in solution (~80% vs ~50%), we have performed molecular dynamics (MD) simulations for ~10 ns of the model in order to explore the dynamic behavior of the single apoA-I monomer at a physiological salt concentration and a temperature range of 310-410 K.
While 10 ns simulation is only a starting point, a few important observations have been made: i) the percentage of alpha helicity decreased substantially to below 70% (i.e., towards a lower experimental estimate); ii) the structure became more globular in overall appearance; iii) the flexible N-terminal domain (amino acid residues 1 to 43) has lost most of its alpha helicity; iv) the hydrophobic core of the 4-helix bundle is defined by stacking of a cluster of aromatic amino acid residues, outlined by a shell of aliphatic hydrophobic residues; v) The four helix bundle portion of the simulated structure is clustering around a pronounced stacking of aromatic residues derived from all four helixes and the aromatic cluster is overlaid by a shell of aliphatic hydrophobic residues. We conjecture that this aromatic cluster and its surrounding hydrophobic residues are the driving force for creation of a dynamic (molten globular) four helix bundle arrangement in lipid-free monomeric apoA-I in solution. This work was supported by NIH grant
Molecular Dynamics Simulated Annealing of Phospholipid- rich HDL
No full textAll-atom MD simulations by us of an atomistic double belt model for discoidal HDL produced particles where the apoA-I belt underwent conformational changes coordinated with a distortion of the bilayer disc into a minimal surface patch. Due to short simulations, these particles might represent kinetically trapped intermediates. Here we report all-atom MD simulated annealing as a more robust
approach to particle structure. Temperature jumps, in explicit water without constraints, were performed on the published 100:2 particle (molar ratio = POPC:D40apoA-I). While 525K produced rapid vaporization, three 500K simulations for 20ns produced no vaporization. Analyses of average changes in structural parameters during simulation showed: i) SASA of acyl chains rapidly increased 5-fold, then plateaued, a result of expansion of an intact bilayer. ii) Total
apoA-I helicity decreased from 95% to 72%. iii) SASA of the lipid-associating hydrophobic residues of apoA-I increased 60%. Using
stability at 500K as one measure of helix stability, the figure above shows changes in helicity of individual residues within tandem helical repeats averaged over the three simulations. We conclude
that much of apoA-I in PL-rich HDL has no “fixed” conformation, end domains being more labile than central ones
Molecular dynamics simulations of normal and Milano rotamers of lipid-bound apolipoprotein A-I particles
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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
Molecular Dynamics Simulations of Protein-Encapsulated Lipid Bilayers Converge Rapidly to form Novel Minimal Surfaces
No full textAppropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
Structures of Discoidal High Density Lipoproteins A COMBINED COMPUTATIONAL-EXPERIMENTAL APPROACH
No full textConversion of discoidal phospholipid (PL)-rich high density lipoprotein (HDL) to spheroidal cholesteryl ester-rich HDL is a central step in reverse cholesterol transport. A detailed understanding of this process and the atheroprotective role of apolipoprotein A-I (apoA-I) requires knowledge of the structure and dynamics of these various particles. This study, combining computation with experimentation, illuminates structural features of apoA-I allowing it to incorporate varying amounts of PL. Molecular dynamics simulated annealing of PL-rich HDL models containing unesterified cholesterol results in double belt structures with the same general saddle-shaped conformation of both our previous molecular dynamics simulations at 310 K and the x-ray structure of lipid-free apoA-I. Conversion from a discoidal to a saddle-shaped particle involves loss of helicity and formation of loops in opposing antiparallel parts of the double belt. During surface expansion caused by the temperature-jump step, the curved palmitoyloleoylphosphatidylcholine bilayer surfaces approach planarity. Relaxation back into saddle-shaped structures after cool down and equilibration further supports the saddle-shaped particle model. Our kinetic analyses of reconstituted particles demonstrate that PL-rich particles exist in discrete sizes corresponding to local energetic minima. Agreement of experimental and computational determinations of particle size/shape and apoA-I helicity provide additional support for the saddle-shaped particle model. Truncation experiments combined with simulations suggest that the N-terminal proline-rich domain of apoA-I influences the stability of PL-rich HDL particles. We propose that apoA-I incorporates increasing PL in the form of minimal surface bilayers through the incremental unwinding of an initially twisted saddle-shaped apoA-I double belt structure
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