Analysis of Binding Site Hot Spots on the Surface of Ras GTPase

We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target

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

Observation of the X17 anomaly in the decay of the Giant Dipole Resonance of 8^8Be

Angular correlation spectra of $e^+e^-$ pairs produced in the $^{7}$Li($p$,$\gamma$)$^{8}$Be nuclear reaction were studied at a proton beam energy of $E_p$~=~4.0~MeV, which corresponds to the excitation energy of the Giant Dipole Resonance (GDR) in $^8$Be. The spectra measured show a peak like anomaly at 120$^\circ$ and a broader anomaly also above 140$^\circ$. Both anomalies could consistently be described by assuming that the same hypothetical X17 particle was created both in the ground-state transition and in the transition going to the broad ($\Gamma$=1.5~MeV), first excited state in $^8$Be. The invariant mass of the particle, which was derived to be $m_Xc^2 = 16.95 \pm 0.48$(stat.)~MeV, agrees well with our previously published values.Comment: 5 pages, 7 figures. arXiv admin note: text overlap with arXiv:2209.1079

Phase behaviors of binary mixtures composed of banana-shaped and calamitic mesogens

In this work, five mixtures with different concentrations of banana-shaped and calamitic compounds have been prepared and subsequently studied by polarizing optical microscopy, differential scanning calorimetry, and X-ray diffraction on non-oriented samples. The phase sequences and molecular parameters of the binary systems are presented

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

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

First Year PIDDP Report on gamma-ray and x-ray spectroscopy: X-ray remote sensing and in situ spectroscopy for planetary exploration missions and gamma-ray remote sensing and in situ spectroscopy for planetary exploration missions

Detectors that will be used for planetary missions must have their responses calibrated in a reproducible manner. In addition, it is important to characterize a detector system at uneven portions of its life cycle, for example after exposure to different amounts of radiation. A calibration and response characterization facility has been constructed at Schlumberger-Doll Research for all types of gamma- and x-ray detectors that may be used for planetary measurement. This facility is currently being tested. Initial use is expected for the MARS 94 detectors. The facility will then also be available for calibrating other detectors as well as arrays of detectors such as the NEAR detector with its central Nal(TI) crystal surrounded with a large BGO crystal. Cadmium telluride detectors are investigated for applications in space explorations. These detectors show an energy resolution of 5 keV for the 122 keV 57Co line. Earlier reported polarization effects are not observed. The detectors can be used at temperatures up to 100 C, although with reduced energy resolution. The thickness of standard detectors is limited to 2 mm. These detectors become fully efficient at bias voltages above 200 V. Initial results for a 1 cm thick detector show that the quality of the material is inferior to the thinner standard detectors and hole trapping affects the pulse height. A detailed characterization of the detector is in progress. Prototypes of photomultipliers based on a Channel Electron Multiplier (CEM) are being built to study their performance. Such photomultipliers promise better timing characteristics and a higher dynamic range while being more compact and of lower in weight

Electronic Structure of Lanthanum Hydrides with Switchable Optical Properties

Recent dramatic changes in the optical properties of LaH_{2+x} and YH_{2+x} films discovered by Huiberts et al. suggest their electronic structure is described best by a local model. Electron correlation is important in H^- -centers and in explaining the transparent insulating behavior of LaH_3. The metal-insulator transition at $x\sim 0.8$ takes place in a band of highly localized states centered on the $H$-vacancies in the LaH_3 structure.Comment: plain tex, 3 figure