Encounter complexes and dimensionality reduction in protein-protein association

An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein–protein association using a physics-based energy function. The agreement between experimental intermolecular paramagnetic relaxation enhancement (PRE) data and the PRE profiles calculated from the docked structures shows that the method captures both specific and non-specific encounter complexes. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis. Results show that the energy surface is canyon-like, with a smooth funnel within a two dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition

Lithium colloids and color center creation in electron-irradiated Li2NH observed by electron-spin resonance

4 pagesInternational audienceWe have irradiated Li2NH powder with MeV electrons at room temperature and investigated the introduced defects with electron spin resonance. CESR indicates the presence of nanosize metallic Li colloids seen as a Lorentzian line with a g = 2.0023 and a line width DeltaH = 50 microT. A second, broader, signal (DeltaH = 3 to 4 mT) appears superimposed upon the Li line at low T (Curie-type behavior) which exhibits complex T-dependence with a break near 180 K for its g-value and DeltaH. We are suggesting for the latter a vacancy-type defect in the NH-sublattice, with freezing of its H-component below 180 K. When heated both the Li colloids and the color centers anneal around 100 C probably due to hydrogen evolution and subsequent chemical degradation

The 10Be contents of SNC meteorites

Several authors have explored the possibility that the Shergottites, Nakhlites, and Chassigny (SNC) came from Mars. The spallogenic gas contents of the SNC meteorites have been used to: constrain the sizes of the SNC's during the last few million years; to establish groupings independent of the geochemical ones; and to estimate the likelihood of certain entries in the catalog of all conceivable passages from Mars to Earth. The particular shielding dependence of Be-10 makes the isotope a good probe of the irradiation conditions experienced by the SNC meteorites. The Be-10 contents of nine members of the group were measured using the technique of accelerator mass spectrometry. The Be-10 contents of Nakhla, Governador Valadares, Chassigny, and probably Lafayette, about 20 dpm/kg, exceed the values expected from irradiation of the surface of a large body. The Be-10 data therfore do not support scenario III of Bogard et al., one in which most of the Be-10 in the SNC meteorites would have formed on the Martian surface; they resemble rather the Be-10 contents found in many ordinary chondrites subjected to 4 Pi exposures. The uncertainties of the Be-10 contents lead to appreciable errors in the Be-10 ages, t(1) = -1/lambda ln(1 Be-10/Be-10). Nonetheless, the Be-10 ages are consistent with the Ne-21 ages calculated assuming conventional, small-body production rates and short terrestrial ages for the finds. It is believed that this concordance strengthens the case for at least 3 different irradiation ages for the SNC meteorites. Given the similar half-thicknesses of the Be-10 and Ne-21 production rates, the ratios of the Be-10 and Ne-21 contents do not appear consistent with common ages for any of the groups. In view of the general agreement between the Be-10 and Ne-21 ages it does not seem useful at this time to construct multiple-stage irradiation histories for the SNC meteorites

Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Teratogenic risk and contraceptive counselling in psychiatric practice: analysis of anticonvulsant therapy

<p>Background: Anticonvulsants have been used to manage psychiatric conditions for over 50 years. It is recognised that some, particularly valproate, carbamazepine and lamotrigine, are human teratogens, while others including topiramate require further investigation. We aimed to appraise the documentation of this risk by psychiatrists and review discussion around contraceptive issues.</p> <p>Methods: A retrospective review of prescribing patterns of four anticonvulsants (valproate, carbamazepine, lamotrigine and topiramate) in women of child bearing age was undertaken. Documented evidence of discussion surrounding teratogenicity and contraceptive issues was sought.</p> <p>Results: Valproate was most commonly prescribed (n=67). Evidence of teratogenic risk counselling at medication initiation was sub-optimal – 40% of individuals prescribed carbamazepine and 22% of valproate. Documentation surrounding contraceptive issues was also low- 17% of individuals prescribed carbamazepine and 13% of valproate.</p> <p>Conclusion: We found both low rates of teratogenic risk counselling and low rates of contraception advice in our cohort. Given the high rates of unplanned pregnancies combined with the relatively high risk of major congenital malformations, it is essential that a detailed appraisal of the risks and benefits associated with anticonvulsant medication occurs and is documented within patients’ psychiatric notes.</p&gt

Hydrogen Bond Dynamics Near A Micellar Surface: Origin of the Universal Slow Relaxation at Complex Aqueous Interfaces

The dynamics of hydrogen bonds among water molecules themselves and with the polar head groups (PHG) at a micellar surface have been investigated by long molecular dynamics simulations. The lifetime of the hydrogen bond between a PHG and a water molecule is found to be much longer than that between any two water molecules, and is likely to be a general feature of hydrophilic surfaces of organized assemblies. Analyses of individual water trajectories suggest that water molecules can remain bound to the micellar surface for more than a hundred picosecond. The activation energy for such a transition from the bound to a free state for the water molecules is estimated to be about 3.5kcal/mole.Comment: 12 pages. Phys. Rev. Lett. (Accepted) (2002

Yang-Lee zeros for a nonequilibrium phase transition

Equilibrium systems which exhibit a phase transition can be studied by investigating the complex zeros of the partition function. This method, pioneered by Yang and Lee, has been widely used in equilibrium statistical physics. We show that an analogous treatment is possible for a nonequilibrium phase transition into an absorbing state. By investigating the complex zeros of the survival probability of directed percolation processes we demonstrate that the zeros provide information about universal properties. Moreover we identify certain non-trivial points where the survival probability for bond percolation can be computed exactly.Comment: LaTeX, IOP-style, 13 pages, 10 eps figure

Thermal regimes of HTS cylinders operating in devices for fault current limitation

We reveal obstacles related to the application of HTS cylinders in current limiting devices based on the superconducting - normal state transition. It is shown that, at the critical current density achieved presently in bulk materials, and especially in BSCCO-2212, the required thickness of the cylinder wall in a full-scale inductive device achieves several centimeters. A simple mathematical model of the operation of an inductive fault current limiter (FCL) is used to show that such cylinders cannot be cooled in admissible time after a fault clearing and, hence, the inductive FCLs and current-limiting transformers employing BSCCO cylinders do not return to the normal operation in the time required. For the recovery even with a non-current pause in the circuit, the cylinders are needed with the critical current density by an order higher than the existed ones.Comment: 15 pages, 5 figure

Beable trajectories for revealing quantum control mechanisms

The dynamics induced while controlling quantum systems by optimally shaped laser pulses have often been difficult to understand in detail. A method is presented for quantifying the importance of specific sequences of quantum transitions involved in the control process. The method is based on a ``beable'' formulation of quantum mechanics due to John Bell that rigorously maps the quantum evolution onto an ensemble of stochastic trajectories over a classical state space. Detailed mechanism identification is illustrated with a model 7-level system. A general procedure is presented to extract mechanism information directly from closed-loop control experiments. Application to simulated experimental data for the model system proves robust with up to 25% noise.Comment: Latex, 20 pages, 13 figure