Predicting Transcription Factor Specificity with All-Atom Models

The binding of a transcription factor (TF) to a DNA operator site can initiate or repress the expression of a gene. Computational prediction of sites recognized by a TF has traditionally relied upon knowledge of several cognate sites, rather than an ab initio approach. Here, we examine the possibility of using structure-based energy calculations that require no knowledge of bound sites but rather start with the structure of a protein-DNA complex. We study the PurR E. coli TF, and explore to which extent atomistic models of protein-DNA complexes can be used to distinguish between cognate and non-cognate DNA sites. Particular emphasis is placed on systematic evaluation of this approach by comparing its performance with bioinformatic methods, by testing it against random decoys and sites of homologous TFs. We also examine a set of experimental mutations in both DNA and the protein. Using our explicit estimates of energy, we show that the specificity for PurR is dominated by direct protein-DNA interactions, and weakly influenced by bending of DNA.Comment: 26 pages, 3 figure

Casimir forces between cylinders and plates

We study collective interaction effects that result from the change of free quantum electrodynamic field fluctuations by one- and two-dimensional perfect metal structures. The Casimir interactions in geometries containing plates and cylinders is explicitly computed using partial wave expansions of constrained path integrals. We generalize previously obtained results and provide a more detailed description of the technical aspects of the approach \cite{Emig06}. We find that the interactions involving cylinders have a weak logarithmic dependence on the cylinder radius, reflecting that one-dimensional perturbations are marginally relevant in 4D space-time. For geometries containing two cylinders and one or two plates, we confirm a previously found non-monotonic dependence of the interaction on the object's separations which does not follow from pair-wise summation of two-body forces. Qualitatively, this effect is explained in terms of fluctuating charges and currents and their mirror images

Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

A simplified version of rapid susceptibility testing of bacteria and yeasts using optical nanomotion detection

We present a novel optical nanomotion-based rapid antibiotic and antifungal susceptibility test. The technique consisted of studying the effects of antibiotics or antifungals on the nanometric scale displacements of bacteria or yeasts to assess their sensitivity or resistance to drugs. The technique relies on a traditional optical microscope, a video camera, and custom-made image analysis software. It provides reliable results in a time frame of 2–4 h and can be applied to motile, non-motile, fast, and slowly growing microorganisms. Due to its extreme simplicity and low cost, the technique can be easily implemented in laboratories and medical centers in developing countries

Scattering theory approach to electrodynamic Casimir forces

We give a comprehensive presentation of methods for calculating the Casimir force to arbitrary accuracy, for any number of objects, arbitrary shapes, susceptibility functions, and separations. The technique is applicable to objects immersed in media other than vacuum, nonzero temperatures, and spatial arrangements in which one object is enclosed in another. Our method combines each object’s classical electromagnetic scattering amplitude with universal translation matrices, which convert between the bases used to calculate scattering for each object, but are otherwise independent of the details of the individual objects. The method is illustrated by rederiving the Lifshitz formula for infinite half-spaces, by demonstrating the Casimir-Polder to van der Waals crossover, and by computing the Casimir interaction energy of two infinite, parallel, perfect metal cylinders either inside or outside one another. Furthermore, it is used to obtain new results, namely, the Casimir energies of a sphere or a cylinder opposite a plate, all with finite permittivity and permeability, to leading order at large separation