Implicit Ligand Theory: Rigorous Binding Free Energies and Thermodynamic Expectations from Molecular Docking

A rigorous formalism for estimating noncovalent binding free energies and thermodynamic expectations from calculations in which receptor configurations are sampled independently from the ligand is derived. Due to this separation, receptor configurations only need to be sampled once, facilitating the use of binding free energy calculations in virtual screening. Demonstrative calculations on a host-guest system yield good agreement with previous free energy calculations and isothermal titration calorimetry measurements. Implicit ligand theory provides guidance on how to improve existing molecular docking algorithms and insight into the concepts of induced fit and conformational selection in noncovalent macromolecular recognition.Comment: 21 pages, 2 figures, 4 tables, 3 supplemental figures, 2 supplemental table

Optimized replica gas estimation of absolute integrals and partition functions

In contrast with most Monte Carlo integration algorithms, which are used to estimate ratios, the replica gas identities recently introduced by Adib enable the estimation of absolute integrals and partition functions using multiple copies of a system and normalized transition functions. Here, an optimized form is presented. After generalizing a replica gas identity with an arbitrary weighting function, we obtain a functional form that has the minimal asymptotic variance for samples from two replicas and is provably good for a larger number. This equation is demonstrated to improve the convergence of partition function estimates in a 2D Ising model.Comment: 8 pages, 2 figure

Determinants of Foreign Direct Investment in the Food Manufacturing Industry

This paper examines firm-specific characteristics in the food manufacturing industry that affect firms' decisions in accessing foreign markets via foreign direct investment (FDI). It also seeks to assess variations in the intensity level of multinational firm involvement in FDI given these characteristics. It finds that capital-intensive firms with higher levels of intangible assets, profitability, and knowledge capital are more likely to be MNEs. It also finds that intangible assets and knowledge capital underline the tendency of MNEs to invest more intensively abroad. Furthermore, firm size is found to play an important but not necessarily dominant role in FDI propensity and intensity.Agribusiness,

Childhood Overweight and School Outcomes

This paper investigates the association between weight and elementary school students’ academic achievement, as measured by standardized Item Respond Theory scale scores in reading and math. Data for this study come from the 1998 cohort of the Early Childhood Longitudinal Study, Kindergarten-Fifth Grade (ECLS-K), which contains a large national sample of children between the ages of 5 and 12. Estimates of the association between weight and achievement were obtained by utilizing two regression model specifications, a mixed-effects linear model and a student-specific fixed-effects model. A comprehensive set of explanatory variables such as a household’s motivation in helping the student learn (e.g. parents’ expectations for their child’s schooling and levels of parental involvement with school activities), teacher qualification, and school characteristics are controlled for. The results show that malnourished children, both underweight and overweight, especially obese, achieve lower scores on standardized tests, particularly for mathematics, when compared to normal weight children. The outcomes are more pronounced for female students compared to male students. These results emphasize the need to reduce childhood malnutrition, especially childhood obesity.Childhood overweight, academic achievement, ECLS-K, Consumer/Household Economics, Teaching/Communication/Extension/Profession,

Do Eating Patterns Follow a Cohort or Change Over a Lifetime? Answers Emerging from the Literature

With the rapidly increasing American elderly population, food companies, healthcare workers, and policy makers alike are asking whether the dietary habits and food consumption patterns of this growing segment of the U.S. population will follow those of current and past elderly people or whether their cohort will eat like they did when they were younger. The purpose of this report is to review what is known about changes in nutritional intake and food consumption patterns that are associated with cohorts (generational) and with the aging process in the U.S. population. Recent literature on cohort and aging effects related to food consumption indicates that the aging effect is greater than the cohort effect. That is, diets change as people age, due to factors such as food availability, new information, new cumulative experiences, and physiological changes as bodies mature. Cohort effect is more likely due to changes in income, i.e., each succeeding cohort realizing higher real per capita income. Variation in findings is likely due to different data sources and analytic methods. Information on data sources and common databases used in these types of studies are also reviewed.Food consumption, cohort, age effect, Food Consumption/Nutrition/Food Safety,

Nonequilibrium candidate Monte Carlo: A new tool for efficient equilibrium simulation

Metropolis Monte Carlo simulation is a powerful tool for studying the equilibrium properties of matter. In complex condensed-phase systems, however, it is difficult to design Monte Carlo moves with high acceptance probabilities that also rapidly sample uncorrelated configurations. Here, we introduce a new class of moves based on nonequilibrium dynamics: candidate configurations are generated through a finite-time process in which a system is actively driven out of equilibrium, and accepted with criteria that preserve the equilibrium distribution. The acceptance rule is similar to the Metropolis acceptance probability, but related to the nonequilibrium work rather than the instantaneous energy difference. Our method is applicable to sampling from both a single thermodynamic state or a mixture of thermodynamic states, and allows both coordinates and thermodynamic parameters to be driven in nonequilibrium proposals. While generating finite-time switching trajectories incurs an additional cost, driving some degrees of freedom while allowing others to evolve naturally can lead to large enhancements in acceptance probabilities, greatly reducing structural correlation times. Using nonequilibrium driven processes vastly expands the repertoire of useful Monte Carlo proposals in simulations of dense solvated systems

Effective Approaches to Attention-based Neural Machine Translation

An attentional mechanism has lately been used to improve neural machine translation (NMT) by selectively focusing on parts of the source sentence during translation. However, there has been little work exploring useful architectures for attention-based NMT. This paper examines two simple and effective classes of attentional mechanism: a global approach which always attends to all source words and a local one that only looks at a subset of source words at a time. We demonstrate the effectiveness of both approaches over the WMT translation tasks between English and German in both directions. With local attention, we achieve a significant gain of 5.0 BLEU points over non-attentional systems which already incorporate known techniques such as dropout. Our ensemble model using different attention architectures has established a new state-of-the-art result in the WMT'15 English to German translation task with 25.9 BLEU points, an improvement of 1.0 BLEU points over the existing best system backed by NMT and an n-gram reranker.Comment: 11 pages, 7 figures, EMNLP 2015 camera-ready version, more training detail

Alchemical Grid Dock (AlGDock): Binding Free Energy Calculations between Flexible Ligands and Rigid Receptors

Alchemical Grid Dock (AlGDock) is open-source software designed to compute the binding potential of mean force (BPMF) - the binding free energy between a flexible ligand and a rigid receptor - for a small organic ligand and a biological macromolecule. Multiple BPMFs can be used to rigorously compute binding affinities between flexible partners. AlGDock uses replica exchange between thermodynamic states at different temperatures and receptor-ligand interaction strengths. Receptor-ligand interaction energies are represented by interpolating precomputed grids. Thermodynamic states are adaptively initialized and adjusted on-the-fly to maintain replica exchange rates. In demonstrative calculations, when the bound ligand is treated as fully solvated, AlGDock estimates BPMFs with a precision within 4 kT in 65% and within 8 kT for 91% of systems. It correctly identifies the native binding pose in 83% of simulations. Performance is sometimes limited by subtle differences in the important configuration space of sampled and targeted thermodynamic states.Comment: 53 pages, 12 figures, 4 supplemental figure