The conformational preferences of epothilone A (EPA) and a 12,13-cyclopropyl C12-epimerized analogue were explored in aqueous solution using molecular dynamics simulations. The simulated conformers that provided an optimal fit in the paclitaxel binding site of mammalian β-tubulin were then selected. The resulting modeled complexes were simulated before and after refinement of the M-loop to improve the fitting and assess ligand stability within the binding pocket. The tubulin-bound conformation of EPA was found to be unlike a previously reported solution obtained through mixed crystallographic/NMR/modeling studies. However, our conformation was in agreement with an NMR-based proposal although the exact binding pose within the site was different. Molecular models were built for the complexes of 14 epothilone derivatives with β-tubulin. A projection to latent structures regression method succeeded in providing a good prediction of the experimentally measured binding enthalpies for the whole set of ligands by assigning weights to a selection of interaction energy terms. These receptor-based, quantitative structure-activity relationships support the proposed binding mode, help confirm and interpret previously acquired experimental data, shed additional light on the effect of several β-tubulin mutations on ligand binding, and can potentially direct further experimental studies.

A new approach is presented that combines structure- and ligand-based virtual screening in a reverse way. Opposite to the majority of the methods, a docking protocol is first employed to prioritize small ligands ("fragments") that are subsequently used as queries to search for similar larger ligands in a database. For a given chemical library, a three-step strategy is followed consisting of (1) contraction into a representative, non-redundant, set of fragments,(2) selection of the three best-scoring fragments docking into a given macromolecular target site, and (3) expansion of the fragments' structures back into ligands by using them as queries to search the library by means of fingerprint descriptions and similarity criteria. We tested the performance of this approach on a collection of fragments and ligands found in the ZINC database and the directory of useful decoys, and compared the results with those obtained using a standard docking protocol. The new method provided better overall results and was several times faster. We also studied the chemical diversity that both methods cover using an in-house compound library and concluded that the novel approach performs similarly but at a much smaller computational cost.

Flow coefficients v_{n} for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at sqrt[s_{NN}]=200  GeV, are measured relative to event planes Ψ_{n}, determined at large rapidity. We report v_{n} as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The v_{n} are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio η/s.

Mitomycin C (MMC) is a potent antitumour agent that forms a covalent bond with the 2-amino group of selected guanines in the minor groove of double-stranded DNA following intracellular reduction of its quinone ring and opening of its aziridine moiety. At some 5'-CG-3'(CpG) steps the resulting monofunctional adduct can evolve towards a more deleterious bifunctional lesion, which is known as an interstrand crosslink (ICL). MMC reactivity is enhanced when the cytosine bases are methylated (5 MC) and decreased when they are replaced with 5-F-cytosine (5FC) whereas the stereochemical preference of alkylation changes upon decarbamoylation. We have studied three duplex oligonucleotides of general formula d(CGATAAXGCTAACG) in which X stands for C, 5MC or 5FC. Using a combination of molecular dynamics simulations in aqueous solution, quantum mechanics and continuum electrostatics, we have been able to (i) obtain a large series of snapshots that facilitate an understanding in atomic detail of the distinct stereochemistry of monoadduct and ICL formation by MMC and its decarbamoylated analogue,(ii) provide an explanation for the altered reactivity of MMC towards DNA molecules containing 5MC or 5FC, and (iii) show the distinct accommodation in the DNA minor groove of the different covalent modifications, particularly the most cytotoxic C1α and C1β ICLs.

Synaptic glycine levels are controlled by glycine transporters (GLYTs). GLYT1 is the main regulator of synaptic glycine concentrations, which catalyzes Na+/Cl-/glycine cotransport with a 2:1:1 stoichiometry. By contrast, neuronal GLYT2 supplies glycine to the presynaptic terminal with a 3:1:1 stoichiometry. We subjected homology models of GLYT1 and GLYT2 to molecular dynamics simulations in the presence of Na+. Using Molecular Interaction Potential maps and in silico mutagenesis, we identified a conserved region in the GLYT2 external vestibule likely to be involved in Na+ interactions. Replacement of D471 in this region reduced Na+ affinity and Na+ cooperativity of transport, an effect not produced in the homologous position (D295) in GLYT1. Unlike the GLYT1D295 mutation, this D471 mutant increased sodium leakage and non-stoichiometric uncoupled ion movements through GLYT2, as determined by simultaneously measuring current and [3H]glycine accumulation. The homologous D471 and D295 positions exhibited distinct cation-sensitive external accessibility, and they were involved in Na+ and Li+-induced conformational changes. While these two cations had opposite effects on GLYT1 they had comparable effects on accessibility in GLYT2, explaining the inhibitory and stimulatory responses to lithium exhibited by the two transporters. Based on these findings, we propose a role for D471 in controlling cation access to GLYT2 Na+ sites, ion coupling during transport and the subsequent conformational changes.

Back-to-back hadron pair yields in d+Au and p+p collisions at √s(NN)=200 GeV were measured with the PHENIX detector at the Relativistic Heavy Ion Collider. Rapidity separated hadron pairs were detected with the trigger hadron at pseudorapidity |η|<0.35 and the associated hadron at forward rapidity (deuteron direction, 3.0<η<3.8). Pairs were also detected with both hadrons measured at forward rapidity; in this case, the yield of back-to-back hadron pairs in d+Au collisions with small impact parameters is observed to be suppressed by a factor of 10 relative to p+p collisions. The kinematics of these pairs is expected to probe partons in the Au nucleus with a low fraction x of the nucleon momenta, where the gluon densities rise sharply. The observed suppression as a function of nuclear thickness, p(T), and η points to cold nuclear matter effects arising at high parton densities.

We present measurements of J/ψ yields in d+Au collisions at sqrt[s(NN)]=200  GeV recorded by the PHENIX experiment and compare them with yields in p+p collisions at the same energy per nucleon-nucleon collision. The measurements cover a large kinematic range in J/ψ rapidity (-2.2<y<2.4) with high statistical precision and are compared with two theoretical models: one with nuclear shadowing combined with final state breakup and one with coherent gluon saturation effects. In order to remove model dependent systematic uncertainties we also compare the data to a simple geometric model. The forward rapidity data are inconsistent with nuclear modifications that are linear or exponential in the density weighted longitudinal thickness, such as those from the final state breakup of the bound state.

The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α1β1 � α2β2) has been ascertained by X-ray crystallographic studies on a complex of tubulin with the stathmin-like domain of protein RB3, albeit at relatively low resolution. Here we use molecular modeling and simulation techniques to build, refine and perform a comparative analysis of the three-dimensional complexes of vinblastine, vincristine, vinorelbine and vinflunine with a β1α2-tubulin interface in explicit water to rationalize the binding affinity differences in structural and energetic terms. Our results shed some more light into the binding determinants and the structure-activity relationships of these clinically useful agents.

A graphical user interface (GUI) for our previously published virtual screening (VS) and data management platform VSDMIP (Gil-Redondo et al. J Comput Aided Mol Design, 23:171-184, 2009) that has been developed as a plugin for the popular molecular visualization program PyMOL is presented. In addition, a ligand-based VS module (LBVS) has been implemented that complements the already existing structure-based VS (SBVS) module and can be used in those cases where the receptor's 3D structure is not known or for pre-filtering purposes. This updated version of VSDMIP is placed in the context of similar available software and its LBVS and SBVS capabilities are tested here on a reduced set of the Directory of Useful Decoys database. Comparison of results from both approaches confirms the trend found in previous studies that LBVS outperforms SBVS. We also show that by combining LBVS and SBVS, and using a cluster of ~100 modern processors, it is possible to perform complete VS studies of several million molecules in less than a month. As the main processes in VSDMIP are 100% scalable, more powerful processors and larger clusters would notably decrease this time span. The plugin is distributed under an academic license upon request from the authors.

Technetium-99m is an important medical isotope utilized worldwide in nuclear medicine and is produced from the decay of its parent isotope, molybdenum-99. The online fueling capability and compact fuel of the CANDU(®)(1) reactor allows for the potential production of large quantities of (99)Mo. This paper proposes (99)Mo production strategies using modified target fuel bundles loaded into CANDU fuel channels. Using a small group of channels a yield of 89-113% of the weekly world demand for (99)Mo can be obtained.