Cooperativity in drug-DNA recognition: a molecular dynamics study.

NMR studies have shown that the minor groove-binding ligand Hoechst 33258 binds to the two T4/A4 tracts within the duplex d(CTTTTCGAAAAG)2 in a highly cooperative manner, such that in titration experiments no intermediate 1:1 complex can be detected. The NMR-derived structures of the free DNA and the 2:1 complex have been obtained, but can shed little light on what the origins of this cooperativity may be. Here we present the results of a series of molecular dynamics simulations on the free DNA, the 1:1 complex, and the 2:1 complex, which have been designed to enable us to calculate thermodynamic parameters associated with the molecular recognition events. The results of the molecular dynamics studies confirm that structural factors alone cannot explain the cooperativity observed, indeed when enthalpic and hydration factors are looked at in isolation, the recognition process is predicted to be slightly anticooperative. However, when changes in configurational entropy are taken into account as well, the overall free energy differences are such that the calculated cooperativity is in good agreement with that observed experimentally. The results indicate the power of molecular dynamics methods to provide reasonable explanations for phenomena that are difficult to explain on the basis of static models alone, and provide a nice example of the concept of "allostery without conformational change".     

Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C90H48 PAH

Herein, we have synthesized an enantiomerically pure propeller-shaped PAH, C₉₀H₄₈, possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two-photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single-crystal X-ray diffraction analysis.     

How good are SPT schedules for fair optimality criteria

We consider the following scheduling setting: a set of n tasks have to be executed on a set of m identical machines. It is well known that shortest processing time (SPT) schedules are optimal for the problem of minimizing the total sum of completion times of the tasks. In this paper, we measure the quality of SPT schedules, from an approximation point of view, with respect to the following optimality criteria: sum of completion times per machine, global fairness, and individual fairness.     

Photoreactive stapled BH3 peptides to dissect the BCL-2 family interactome

Defining protein interactions forms the basis for discovery of biological pathways, disease mechanisms, and opportunities for therapeutic intervention. To harness the robust binding affinity and selectivity of structured peptides for interactome discovery, we engineered photoreactive stapled BH3 peptide helices that covalently capture their physiologic BCL-2 family targets. The crosslinking α helices covalently trap both static and dynamic protein interactors, and enable rapid identification of interaction sites, providing a critical link between interactome discovery and targeted drug design.     

The Effect of Branching on the One- and Two-Photon Absorption,Cell Viability,and Localization of Cationic Triarylborane Chromophores with Dipolar versus Octupolar Charge Distributions for Cellular Imaging

Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two-photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two-photon excited fluorescence (TPEF) live-cell imaging.     

A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1-Dependent Leukemia Cell Survival

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Highlights? A stapled peptide-based screen identified a selective molecular inhibitor of MCL-1 ? MIM1 targets a subregion of the BH3-binding pocket of antiapoptotic MCL-1 ? In contrast to ABT-737, MIM1 binds and functionally neutralizes MCL-1 but not BCL-X_L ? MIM1 exhibits MCL-1-dependent antileukemia activity and synergizes with ABT-737     

Multimodal Interaction with BCL-2 Family Proteins Underlies the Proapoptotic Activity of PUMA BH3

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Bicriteria scheduling for contiguous and non contiguous parallel tasks

We study the problem of scheduling on k identical machines a set of parallel tasks with release dates and deadlines in order to maximize simultaneously two criteria, namely the Size (number of scheduled tasks) and the Weight (sum of the weights of scheduled tasks). If no task requires more than half of the machines, we construct schedules that are simultaneously approximations for the Size and the Weight by combining two approximate schedules, one for each parameter. We obtain existence results and polynomial time bicriteria approximation algorithms in contiguous and non contiguous models.