Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized

Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge based potentials based on pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state -- a necessary component of these potentials -- is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities reference ratio distributions deriving from the application of the reference ratio method. This new view is not only of theoretical relevance, but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures

Effective index approximations of photonic crystal slabs: a 2-to-1-D assessment

The optical properties of slab-like photonic crystals are often discussed on the basis of effective index (EI) approximations, where a 2-D effective refractive index profile replaces the actual 3-D structure. Our aim is to assess this approximation by analogous steps that reduce finite 2-D waveguide Bragg-gratings (to be seen as sections through 3-D PC slabs and membranes) to 1-D problems, which are tractable by common transfer matrix methods. Application of the EI method is disputable in particular in cases where locally no guided modes are supported, as in the holes of a PC membrane. A variational procedure permits to derive suitable effective permittivities even in these cases. Depending on the structural properties, these values can well turn out to be lower than one, or even be negative. Both the “standard” and the variational procedures are compared with reference data, generated by a rigorous 2-D Helmholtz solver, for a series of example structures.\u

A mass action model of a fibroblast growth factor signaling pathway and its simplification

We consider a kinetic law of mass action model for Fibroblast Growth Factor (FGF) signaling, focusing on the induction of the RAS-MAP kinase pathway via GRB2 binding. Our biologically simple model suffers a combinatorial explosion in the number of differential equations required to simulate the system. In addition to numerically solving the full model, we show that it can be accurately simplified. This requires combining matched asymptotics, the quasi-steady state hypothesis, and the fact subsets of the equations decouple asymptotically. Both the full and simplified models reproduce the qualitative dynamics observed experimentally and in previous stochastic models. The simplified model also elucidates both the qualitative features of GRB2 binding and the complex relationship between SHP2 levels, the rate SHP2 induces dephosphorylation and levels of bound GRB2. In addition to providing insight into the important and redundant features of FGF signaling, such work further highlights the usefulness of numerous simplification techniques in the study of mass action models of signal transduction, as also illustrated recently by Borisov and co-workers (Borisov et al. in Biophys. J. 89, 951–66, 2005, Biosystems 83, 152–66, 2006; Kiyatkin et al. in J. Biol. Chem. 281, 19925–9938, 2006). These developments will facilitate the construction of tractable models of FGF signaling, incorporating further biological realism, such as spatial effects or realistic binding stoichiometries, despite a more severe combinatorial explosion associated with the latter

Unbounded Human Learning: Optimal Scheduling for Spaced Repetition

In the study of human learning, there is broad evidence that our ability to retain information improves with repeated exposure and decays with delay since last exposure. This plays a crucial role in the design of educational software, leading to a trade-off between teaching new material and reviewing what has already been taught. A common way to balance this trade-off is spaced repetition, which uses periodic review of content to improve long-term retention. Though spaced repetition is widely used in practice, e.g., in electronic flashcard software, there is little formal understanding of the design of these systems. Our paper addresses this gap in three ways. First, we mine log data from spaced repetition software to establish the functional dependence of retention on reinforcement and delay. Second, we use this memory model to develop a stochastic model for spaced repetition systems. We propose a queueing network model of the Leitner system for reviewing flashcards, along with a heuristic approximation that admits a tractable optimization problem for review scheduling. Finally, we empirically evaluate our queueing model through a Mechanical Turk experiment, verifying a key qualitative prediction of our model: the existence of a sharp phase transition in learning outcomes upon increasing the rate of new item introductions.Comment: Accepted to the ACM SIGKDD Conference on Knowledge Discovery and Data Mining 201