Science Concentrates

Light shed on hepatitis C replication

Scientists have produced the first molecular-level glimpse at a protein that plays a crucial role in replication of the hepatitis C virus (HCV) (Nature 2005, 435, 374). Nearly 3% of the world's population is infected with HCV, which can lead to cirrhosis and liver cancer. Charles M. Rice, Timothy L. Tellinghuisen, and Joseph Marcotrigiano of Rockefeller University hope that their crystal structure of a portion of NS5A--an active component of the multisubunit machine that HCV uses to replicate its RNA genome--will lead not only to a better understanding of how HCV replicates itself but also to the development of replication inhibitors to combat HCV infections. Their 2.5-Å-resolution structure (shown) reveals that domain I of NS5A has a novel fold, an unexpected disulfide bond, and an unusual four-cysteine zinc-coordination motif. The researchers suggest that the protein's zinc (yellow sphere) plays a structural, not catalytic, role. In the crystal, two molecules of domain I are packed against each other to create a deep groove that might bind RNA to be replicated, they propose.

Alternative to thiol monolayer

A variety of secondary amines condense with carbon disulfide (CS₂) onto gold surfaces at room temperature, forming dithiocarbamate (DTC) monolayers that are considerably more robust than alkanethiol monolayers, according to a new study (J. Am. Chem. Soc. 2005, 127, 7328). Alexander Wei of Purdue University and coworkers produce the film simply by immersing a gold substrate into a solution containing an equimolar ratio of the amine and CS₂. Depending on the amine used, the gold surface can thus be made more hydrophilic or hydrophobic. The researchers report that the dithiocarbamates, which are stable in acidic and basic aqueous environments, adsorb strongly and resist being displaced by competing alkanethiols. For example, when a monolayer of dibutyl DTC (shown) was exposed for 24 hours to a solution of 2-mercaptoethanol, which is known to completely displace alkanethiol monolayers, the DTC monolayer remained essentially intact. Wei believes that these ligands show particular promise for functionalizing surfaces exposed to relatively harsh environmental conditions.

Accounting for OH radicals

Considerably more hydroxyl radicals may be generated in the atmosphere than previously thought, a new study suggests. Hydroxyl radicals cleanse the atmosphere by attacking pollutants. Accurate modeling of atmospheric chemistry requires proper accounting of OH radicals. Jamie Matthews and Amitabha Sinha of the University of California, San Diego, and Joseph S. Francisco of Purdue University propose that a previously ignored source--dissociation through so-called weak electronic absorptions--can augment OH radical formation from hydroperoxides by up to 20% (Proc. Natl. Acad. Sci. USA 2005, 102, 7449). This source has been neglected because the weak absorptions have been difficult to quantify by conventional absorption spectroscopy, Sinha says. In the lower atmosphere, however, the high solar flux (sunlight intensity) in the 360-630-nm region makes these absorptions important. The researchers used a sensitive laser technique to characterize the minute quantities of radiation absorbed by methyl hydroperoxide when it photolyzes to form OH radicals. They believe the technique can be used with other OH radical sources.

Simpler strategy for direct C-C coupling

A new type of selective C-C bond-forming reaction has been devised in which C-H bonds of two molecules cross-couple together in the simplest way possible to construct complex organic molecules of pharmaceutical interest. The "cross-dehydrogenative coupling" (CDC) reaction, developed by Zhiping Li and Chao-Jun Li of McGill University, in Montreal, eliminates the need to first functionalize molecules before they can be coupled together and avoids the need for secondary elimination or hydrogenation reactions. Overall, the strategy makes synthetic schemes shorter and more efficient, the researchers note. They recently reported CDC reactions between sp³ and sp carbon atoms and between sp³ and sp³ carbon atoms, and now report examples of sp³­sp² coupling (J. Am. Chem. Soc. 2005, 127, 6968). In the indolyl tetrahydroisoquinoline derivative shown, the red bond comes from a CDC reaction between the sp³ C­H bond of a quinoline and an aryl sp² C-H bond of an indole. CDC reactions are carried out under mild conditions and are catalyzed by relatively inexpensive copper bromide.

tRNA promotes translational accuracy

Protein biosynthesis is subject to rigorous quality control to prevent missense errors, but the mechanisms to achieve this goal are not yet totally understood. Luisa Cochella and Rachel Green at Johns Hopkins University School of Medicine have now found that tRNAs play an unexpectedly active role in the quality-control process (Science 2005, 308, 1178). Each tRNA is supplied to the ribosome as a complex that must be dismantled before translation can proceed, providing a "proofreading" delay that gives mismatched tRNA extra time to dissociate from the ribosome. The fidelity of translation is further enhanced by ribosome conformational changes induced by tRNA binding, a process called "induced fit." Cochella and Green find that the physical basis for induced fit depends on active conformational contributions made by tRNA upon binding. The study makes it "increasingly clear that, far from being a rigid and passive substrate, tRNA has coevolved with the ribosome to allow the close and dynamic interplay required for the fidelity and speed of translation," a Science commentary notes.