Structure-guided optimization of small molecule c-Abl activators

c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of the autoinhibited conformation or by simply providing no stabilizing interactions to the bent conformation of this helix. Structure-based molecular modeling guided the optimization of binding and activation of c-Abl of these two chemical series and led to the discovery of c-Abl activators with nanomolar potency. The small molecule c-Abl activators reported herein could be used as molecular tools to investigate the biological functions of c-Abl and therapeutic implications of its activation.     

Identification of Metal Contaminants on FCC Catalyst

FCC Catalyst deactivation is a major source of expense in the refining industry. Of concern is the deposition of contaminant metals onto the catalyst particles, leading to premature deactivation. Samples of used catalyst were collected from a working refinery using the standard sampling ports. These samples were subjected to surface examination by Scanning Electron Microscope, and to X‐ray Micro Analysis to determine elementary composition of key metals. Particle mapping was conducted to obtain cross sectional composition of both used and fresh catalyst. It was found that metals preferentially deposit onto the outside of the catalyst particles, presumably causing premature de‐activation to occur. Although the particles are found in a high attrition environment, the metal deposits formed a rough outer surface on the particle. Mild attrition of these particles was found to remove this outside layer of material and help to restore the original chemical make up of the particles surface. This work has shown how refineries can investigate metal deposition onto particles surfaces which will help them better manage FCCU catalyst usage.     

Quantitative microarray profiling of DNA-binding molecules

A high-throughput Cognate Site Identity (CSI) microarray platform interrogating all 524 800 10-base pair variable sites is correlated to quantitative DNase I footprinting data of DNA binding pyrrole-imidazole polyamides. An eight-ring hairpin polyamide programmed to target the 5 bp sequence 5'-TACGT-3' within the hypoxia response element (HRE) yielded a CSI microarray-derived sequence motif of 5'-WWACGT-3' (W = A,T). A linear beta-linked polyamide programmed to target a (GAA)3 repeat yielded a CSI microarray-derived sequence motif of 5'-AARAARWWG-3' (R = G,A). Quantitative DNase I footprinting of selected sequences from each microarray experiment enabled quantitative prediction of Ka values across the microarray intensity spectrum.     

Resolutions of the Coulomb operator: VIII. Parallel implementation using the modern programming language X10

Use of the modern parallel programming language X10 for computing long‐range Coulomb and exchange interactions is presented. By using X10, a partitioned global address space language with support for task parallelism and the explicit representation of data locality, the resolution of the Ewald operator can be parallelized in a straightforward manner including use of both intranode and internode parallelism. We evaluate four different schemes for dynamic load balancing of integral calculation using X10's work stealing runtime, and report performance results for long‐range HF energy calculation of large molecule/high quality basis running on up to 1024 cores of a high performance cluster machine. © 2014 Wiley Periodicals, Inc.     

Distortion of Surface Groups in CAT(0) free-by-cyclic Groups

Given a non-positively curved 2-complex with a circle-valued Morse function satisfying some extra combinatorial conditions, we describe how to locally isometrically embed this in a larger non-positively curved 2-complex with free-by-cyclic fundamental group. This embedding procedure is used to produce examples of CAT(0) free-by-cyclic groups that contain closed hyperbolic surface subgroups with polynomial distortion of arbitrary degree. We also produce examples of CAT(0) hyperbolic free-by-cyclic groups that contain closed hyperbolic surface subgroups that are exponentially distorted.     

Compact Toeplitz operators on the Segal-Bargmann space

In this note, we show that Miao and Zheng's characterization of compact operators on the Bergman space of the unit disk that are finite sums of finite products of Toeplitz operators (with each one of the symbols belonging to BT) also holds for the Segal-Bargmann space of Cn.     

Atom-molecule laser fed by stimulated three-body recombination

Using three-body recombination as the underlying process, we propose a method of coherently driving an atomic Bose-Einstein condensate (BEC) into a molecular BEC. Superradiantlike stimulation favors atom-to-molecule transitions when two atomic BECs collide at a resonant kinetic energy, the result being two molecular BEC clouds moving with well-defined velocities. Potential applications include the construction of a molecule laser.     

Rotational spectrum of the dimethyl ether-acetylene complex: evidence for an effective C2v geometry

The rotational spectra for five isotopomers of the 1:1 weakly bound complex formed between dimethyl ether (DME) and acetylene (HCCH) have been measured by Fourier transform microwave spectroscopy. The experimental rotational constants, planar moments, and dipole moment components are consistent with a floppy complex possessing an effective C2v structure in which the hydrogen atom of acetylene is hydrogen bonded to the oxygen atom of dimethyl ether with an intermolecular H...O separation of 2.08(3) A. Experimental rotational constants for the normal isotopic species are A = 10382.5(17) MHz, B = 1535.7187(18) MHz, and C = 1328.3990(17) MHz and the dipole moment components are mua= mutotal = 1.91(10) D. Ab initio calculations at the MP2/6-311++G(2d,2p) level indicate that the energy barrier for motion of the HCCH subunit between the lone pairs of the DME, via a C2v intermediate structure, is very low (approximately 0.29 kJ mol(-1)). Inclusion of basis set superposition error and zero point energy corrections to the energies of four stationary points located on the potential energy surface shows that the relative stabilities are particularly sensitive to these corrections. The ab initio optimizations give rotational constants for the C2v structure of A = 10066 MHz, B = 1496 MHz, and C = 1324 MHz, and a dipole moment of mua= mu(total) = 2.12 D, in reasonable agreement with the experimentally determined values. The structural parameters and energetics of the DME-HCCH complex will be discussed and compared to similar complexes such as H2O-HCCH.