Development and validation of a modular, extensible docking program: DOCK 5

We report on the development and validation of a new version of DOCK. The algorithm has been rewritten in a modular format, which allows for easy implementation of new scoring functions, sampling methods and analysis tools. We validated the sampling algorithm with a test set of 114 protein-ligand complexes. Using an optimized parameter set, we are able to reproduce the crystal ligand pose to within 2 A of the crystal structure for 79% of the test cases using our rigid ligand docking algorithm with an average run time of 1 min per complex and for 72% of the test cases using our flexible ligand docking algorithm with an average run time of 5 min per complex. Finally, we perform an analysis of the docking failures in the test set and determine that the sampling algorithm is generally sufficient for the binding pose prediction problem for up to 7 rotatable bonds; i.e. 99% of the rigid ligand docking cases and 95% of the flexible ligand docking cases are sampled successfully. We point out that success rates could be improved through more advanced modeling of the receptor prior to docking and through improvement of the force field parameters, particularly for structures containing metal-based cofactors.     

Adsorption of Polyelectrolyte and Nanoparticles at the Silica-Aqueous Solution Interface: Influence of the History of Additions of the Two Components

The interfacial properties of a mixed system of low-charged cationic polyelectrolyte and silica nanoparticles has been studied by means of ellipsometry. Special attention was devoted to the effect that the order of addition of the two components has on the adsorption behavior of the mixed system. Adsorption on silica was in one case studied after simultaneous addition of the components to the aqueous solution. The measured adsorption rates were then much slower than expected for a mass-transfer limited process. This behavior signifies the presence of an electrosteric barrier arising due to preadsorbed polymer-particle complexes. Interfacial layers containing particles were at plateau conditions shown to be highly swollen, whereas the cationic polymer in the particle-free systems adopted a more flat surface conformation. The layer thickness was observed to monotonously increase with an increasing presence of nanoparticles in solution, while the surface excess showed a maximum at intermediate values. The finding was rationalized by the competition between particles and the surface for polymer charges leading to swelling and a decreased effective interaction between polymer and surface. In the other case studied, when polyelectrolyte and nanoparticles were added sequentially, a much more rapid concentration-dependent adsorption was observed. The kinetic adsorption barrier for nonassociated particles was clearly negligible compared with that for the polymer-particle complex. The surface excess did not exhibit an adsorption maximum as a function of added nanoparticles in this situation, indicating that the polymer layer to some degree is irreversibly anchored at the silica surface. Some implications of the above findings for practical papermaking using multicomponent retention systems are put forward. Copyright 2001 Academic Press.     

Threshold kinetic processes for t-C4F9I

A laser oscillator system was used to study the kinetics of t-C₄F₇I relative to n-C₃F₇I. Modeling shows that the rapid R + I¹ recombination results in near steady state gain levels being achieved for t-C₄F₉I while the n-C₃F₇I exhibits strong transient behavior. The estimated recombination rate for t-C₄F₉I is much larger than the published value.     

Efficient formation of uniform-sized embryoid bodies using a compartmentalized microchannel device

The formation of spherical aggregates of cells called embryoid bodies (EBs) is an indispensable step in many protocols in which embryonic stem (ES) cells are differentiated to other cell types. Appropriate morphology and embryo size are critical for the sequential developmental stages of naturally conceived embryos. Likewise, regulating the size of EBs and the timing of their formation is crucial for controlling the differentiation of ES cells within the EB. Existing methods of formation of EBs, however, are tedious or provide heterogeneously-sized EBs. Here we describe a microfluidic system for straightforward synchronized formation of uniform-sized EBs, the size of which can be controlled by changing the cross-sectional size of microchannels in the microfluidic device. The device consists of two microchannels separated by a semi-porous polycarbonate membrane treated to be resistant to cell adhesion. ES cells introduced into the upper channel self-aggregate to form uniformly-sized EBs. The semi-porous membrane also allows subsequent treatment of the non-attached EBs with different reagents from the lower channel without the need for wash out because of the compartmentalization afforded by the membrane. This method provides a simple yet robust means to control the formation of EBs and the subsequent differentiation of ES cells in a format compatible for ES cell processing on a chip.     

Design,Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.     

Enhancement of heavy quarkonium production in hadron collisions at finite temperature

We estimate how the masses and wave functions of heavy quarkonium mesons change with temperature below the deconfining temperatureT _c . To do so we use simple, theoretically motivated parametrizations of the way the heavy quark potential and quark masses vary with temperature. The effect of these changes on the production of charmonium and bottonium in hadron-hadron collisions is estimated using a standard phenomenological model. We find, for example, that forT close toT _c enhancements by as much as a factor of 3 are possible for charmonium and bottonium highp _T production at SPS energies \(\sqrt s\) =20 GeV. Thep _T and energy dependence of this enhancement is non-trivial. We discuss the relevance of our results for the interpretation of recentJ/ψ data from heavy ion collisions.