Studies on Rare-Earth/Iron and Actinide/Iron Multilayers

Hyperfine Interactions - Multilayers of Ce/Fe and U/Fe were fabricated by sputtering and studied by X-ray diffraction and reflectivity, Mössbauer spectroscopy and polarised neutron...     

Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models

Ionizable residues play important roles in protein structure and activity, and proton binding is a valuable reporter of electrostatic interactions in these systems. We use molecular dynamics free energy simulations (MDFE) to compute proton pKa shifts, relative to a model compound in solution, for three aspartate side chains in two proteins. Simulations with explicit solvent and with an implicit, dielectric continuum solvent are reported. The implicit solvent simulations use the generalized Born (GB) model, which provides an approximate, analytical solution to Poisson's equation. With explicit solvent, the direction of the pKa shifts is correct in all three cases with one force field (AMBER) and in two out of three cases with another (CHARMM). For two aspartates, the dielectric response to ionization is found to be linear, even though the separate protein and solvent responses can be nonlinear. For thioredoxin Asp26, nonlinearity arises from the presence of two substates that correspond to the two possible orientations of the protonated carboxylate. For this side chain, which is partly buried and has a large pKa upshift, very long simulations are needed to correctly sample several slow degrees of freedom that reorganize in response to the ionization. Thus, nearby Lys57 rotates to form a salt bridge and becomes buried, while three waters intercalate along the opposite edge of Asp26. Such strong and anisotropic reorganization is very difficult to predict with Poisson-Boltzmann methods that only consider electrostatic interactions and employ a single protein structure. In contrast, MDFE with a GB dielectric continuum solvent, used for the first time for pKa calculations, can describe protein reorganization accurately and gives encouraging agreement with experiment and with the explicit solvent simulations.     

Systematic analysis of the PSI experiment to directly measure the sticking probabilityω s in dt fusion

Starting in 1989 an experiment was run at PSI to directly measure the final sticking probability in muon catalyzed dt fusion. This experiment was based on an active-target ionization chamber (IC) built at Gatchina, Russia, and an array of plastic neutron counters. In three runs approximately 5×10⁶ isolated alpha signals were recorded with around one half of these occurring in the inner chamber region where we have more complete understanding of the systematic errors. Particularly from a long run in 1992 we were able to obtain a very clean sticking peak of some 5000 events. However, to reach an accurate value of sticking, all systematic effects and several major backgrounds had to be understood in detail. To this end a Monte Carlo code was written to simulate the full electrostatic environment of the IC and to recreate completely each signal type including the actual tritium decay noise from the live experiment. A slightly model dependent value of approx. 0.56±0.04% is obtained for final sticking.     

Feasibility of an experiment to determine the branching ratio for the emission of a heavy neutrino after muon capture in3He

The triton energy of the muon capture reaction ³He t+v, where ³ He is the ground state of muonic³He, has been measured in order to investigate a possible heavy v admixture into the flavour with high sensitivity. ³ He has been formed via the pd fusion reaction by stopping ^– in an ionization chamber (IC) filled with an H/D gas mixture of 3% D concentration at a pressure of 161 bar. In a first short experiment 650 triton events were observed yielding an upper limit for the -heavy v mixing strength of 2.3×10^–3 atE _0v=60 MeV.     

Survey of experimental results on μCF including hyperfine effects

Complementary to the investigations of the most efficient dt cycle, also the other muon-induced fusion cycles in mixtures of hydrogen isotopes have been studied. The results of these dedicated experiments provide rich information about muon-induced few-body reactions and contribute significantly to a better overall understanding of CF. A summary of the recent progress will be presented. Special emphasis will be put on two characteristic examples, namely a new experimental approach to study the muonic cascade in H-D mixtures and the systematic study of hyperfine effects in muon-induced reactions.     

The synthesis of some 4,4′-disubstituted-2,2′-biquinolines

2,2′-Biquinoline dioxide and 4,4′-dichloro-2,2′-biquinoline have been used for the preparation of the following 4,4′-disubstituted-2,2′-biquinolines: dimethoxy, diethoxy, dihydroxy, dipiperidino, dipyrrolidino, dibromo, diphenoxy, dithiophenoxy, di(p-chloro-phenoxy), di(p-bromophenoxy), di(p-fluorophenoxy), di(β-naphthoxy) and the dinitro dioxide. Molar extinction coefficients have been determined for several of the copper (I) complexes of these compounds.     

Multi-step polymer-assisted solution-phase (PASP) library synthesis of functionalized diaminobenzamides

A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.     

Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometric analysis of metal-ion selected dynamic protein libraries

The application of electrospray ionization (ESI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry to the investigation of the relative stabilities (and thus packing efficiencies) of Fe-bound trihelix peptide bundles is demonstrated. Small dynamic protein libraries are created by metal-ion assisted assembly of peptide subunits. Control of the trimeric aggregation state is coupled to stability selection by exploiting the coordination requirements of Fe(2+) in the presence of bidentate 2,2'-bipyridyl ligands covalently appended to the peptide monomers. At limiting metal-ion concentration, the most thermodynamically stable, optimally packed peptide trimers dominate the mass spectrum. The identities of optimally stable candidate trimers observed in the ESI FT-ICR mass spectra are confirmed by resynthesis of exchange-inert analogues and measurement of their folding free energies. The peptide composition of the trimers may be determined by infrared multiphoton dissociation (IRMPD) MS(3) experiments. Additional sequence information for the peptide subunits is obtained from electron capture dissociation (ECD) of peptides and metal-bound trimers. The experiments also suggest the presence of secondary structure in the gas phase, possibly due to partial retention of the solution-phase coiled coil structure.     

Stable and efficient algorithms for Xα multiple scattering calculations

Solutions to some practical problems that arise in multiple scattering calculations on large molecules are discussed. (1) Numerical instabilities near the zero of energy can be removed by rescaling the secular matrix. (2) The calculation of structure factors can be made much more efficient by the application of symmetry projection operators. (3) An energy search procedure is described that ensures that no states are inadvertently neglected. Test calculations incorporating these changes illustrate the improved numerical stability, and show decreases in computation time of 30–60%, when compared to previous codes. The procedures suggested here are applicable to both relativistic and nonrelatitistic calculations.     

The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP

In drug discovery, protonation states and tautomerization are easily overlooked. Through a Merck–Rutgers collaboration, this paper re-examined the initial settings and preparations for the Thermodynamic Integration (TI) calculation in AMBER Free-Energy Workflows, demonstrating the value of careful consideration of ligand protonation and tautomer state. Finally, promising results comparing AMBER TI and Schrödinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.