In silico screening of drug-membrane thermodynamics reveals linear relations between bulk partitioning and the potential of mean force

The partitioning of small molecules in cell membranes---a key parameter for pharmaceutical applications---typically relies on experimentally-available bulk partitioning coefficients. Computer simulations provide a structural resolution of the insertion thermodynamics via the potential of mean force, but require significant sampling at the atomistic level. Here, we introduce high-throughput coarse-grained molecular dynamics simulations to screen thermodynamic properties. This application of physics based models in a large-scale study of small molecules establishes linear relationships between partitioning coefficients and key features of the potential of mean force. This allows us to predict the structure of the insertion from bulk experimental measurements for more than 400,000 compounds. The potential of mean force hereby becomes an easily accessible quantity---already recognized for its high predictability of certain properties, e.g., passive permeation. Further, we demonstrate how coarse graining helps reduce the size of chemical space, enabling a hierarchical approach to screening small molecules.Comment: 8 pages, 6 figures. Typos fixed, minor correction

Clustering of Entanglement Points in Highly Strained Polymer Melts

Polymer melts undergoing large deformation by uniaxial elongation are studied by molecular dynamics simulations of bead-spring chains in melts. Applying a primitive path analysis to strongly deformed polymer melts, the role of topological constrains in highly entangled polymer melts is investigated and quantified. We show that the over-all, large scale conformations of the primitive paths (PPs) of stretched chains follow affine deformation while the number and the distribution of entanglement points along the PPs do not. Right after deformation, PPs of chains retract in both directions parallel and perpendicular to the elongation. Upon further relaxation we observe a long-lived clustering of entanglement points. Together with the delayed relaxation time this leads to a metastable inhomogeneous distribution of topological constraints in the melts.Comment: 28 pages, 14 figure

Good Policy or Good Luck? Country Growth Performance and Temporary Shocks

Much of the new growth literature stresses country characteristics, such as education levels or political stability, as the dominant determinant of growth. However, growth rates are highly unstable over time, with a correlation across decades of .1 to .3, while country characteristics are stable, with cross-decade correlations of .6 to .9. Shocks, especially those to terms of trade, play a large role in explaining variance in growth. These findings suggest either that shocks are important relative to country characteristics in determining long-run growth, or that worldwide technological change determines long-run growth while country characteristics determine relative income levels.

Apoptosis in neurodegenerative diseases: to be or not to be? Absence of proof is not proof of absence

Apoptosis (from Greek falling off) is a term coined by Kerr, Wyllie and Currie in 1972 to describe a form of cell death associated with peculiar morphological changes. They contrasted apoptosis with necrosis, in which large numbers of cells undergo destruction and elicit a regional inflammatory response. In contrast, in apoptosis individual cells die and are being removed quickly, without inflammation, making their demise often difficult to detect. The initial concept of apoptosis was exclusively related to a morphological phenomenon.Biomedical Reviews 1995; 4: 103-108

Dynamic characteristics and processing of fillers in polyurethane elastomers for vibration damping applications

Polyurethane elastomers have the potential of being used to reduce vibrational noise in many engineering applications. The performance of the elastomer is directly related to matching the nature of the mechanical loss characteristics to the frequency and temperature dependence of the source of the vibration. Materials with a broad frequency response and good mechanical properties are desirable for situations were load bearing and isolation becomes an issue. Because automobile, and other related vehicles operate over a broad temperature range, it is desirable for the damping characteristics of the elastomer to ideally be independent of temperature and frequency. In practice, this is not possible and the creation of materials with a broad spectrum response is desirable. In this paper, the effects of various fillers on the breadth and temperature dependence of the vibration damping characteristics of a filled and crosslinked polyurethane elastomer are explored. The fillers studied are wollastonite, barium sulphate and talc. These materials have different shapes, sizes and surface chemistry and undergo different types of interaction with the matrix. The vibration damping characteristics were further varied by the use of a crosslinking agent. Data presented on the rheological characteristics indicate the strength of the filler-polyol interactions. Dielectric relaxation and dynamic mechanical thermal analysis demonstrate the way in which changes in the type of filler, concentration and amount of crosslinker lead to changes in the location and breadth of the energy dissipation process in these elastomers. The vibration damping characteristics of a selected material are presented to demonstrate the potential of these materials