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

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.

Inflationary and dark energy regimes in 2+1 dimensions

In this work we investigate the behavior of three-dimensional (3D) cosmological models. The simulation of inflationary and dark-energy-dominated eras are among the possible results in these 3D formulations; taking as starting point the results obtained by Cornish and Frankel. Motivated by those results, we investigate, first, the inflationary case where we consider a two-constituent cosmological fluid: the scalar field represents the hypothetical inflaton which is in gravitational interaction with a matter/radiation contribution. For the description of an old universe, it is possible to simulate its evolution starting with a matter dominated universe that faces a decelerated/accelerated transition due to the presence of the additional constituent (simulated by the scalar field or ruled by an exotic equation of state) that plays the role of dark energy. We obtain, through numerical analysis, the evolution in time of the scale factor, the acceleration, the energy densities, and the hydrostatic pressure of the constituents. The alternative scalar cosmology proposed by Cornish and Frankel is also under investigation in this work. In this case an inflationary model can be constructed when another non-polytropic equation of state (the van der Waals equation) is used to simulate the behavior of an early 3D universe.Comment: Latex file, plus 9 figures. To appear in General Relativity and Gravitatio

Effect of the spin-orbit interaction on the thermodynamic properties of crystals: The specific heat of bismuth

In recent years, there has been increasing interest in the specific heat $C$ of insulators and semiconductors because of the availability of samples with different isotopic masses and the possibility of performing \textit{ab initio} calculations of its temperature dependence $C(T)$ using as a starting point the electronic band structure. Most of the crystals investigated are elemental (e.g., germanium) or binary (e.g., gallium nitride) semiconductors. The initial electronic calculations were performed in the local density approximation and did not include spin-orbit interaction. Agreement between experimental and calculated results was usually found to be good, except for crystals containing heavy atoms (e.g., PbS) for which discrepancies of the order of 20% existed at the low temperature maximum found for $C/T^3$. It has been conjectured that this discrepancies result from the neglect of spin-orbit interaction which is large for heavy atoms ($\Delta_0\sim$1.3eV for the $p$ valence electrons of atomic lead). Here we discuss measurements and \textit{ab initio} calculations of $C(T)$ for crystalline bismuth ($\Delta_0\sim$1.7 eV), strictly speaking a semimetal but in the temperature region accessible to us ($T >$ 2K) acting as a semiconductor. We extend experimental data available in the literature and notice that the \textit{ab initio} calculations without spin-orbit interaction exhibit a maximum at $\sim$8K, about 20% lower than the measured one. Inclusion of spin-orbit interaction decreases the discrepancy markedly: The maximum of $C(T)$ is now only 7% larger than the measured one. Exact agreement is obtained if the spin-orbit hamiltonian is reduced by a factor of $\sim$0.8.Comment: 4 pages, 3 figure

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

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