Spotlights pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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A STAPLED PEPTIDE HELPS CELLS TAKE OUT THE TRASH Autophagy, as it is known, removes damaged organelles, protein aggregates, and other unwanted material from the cell; a slowdown in this process can cause aggregated proteins to accumulate in Alzheimer’s, Parkinson’s, and Huntington’s diseases, and activation of this process can promote clearance of a wide range of bacteria and viruses. As a possible way to treat these diseases, chemists are working to develop compounds that can induce autophagy. One promising candidate, the Tat-Beclin-1 peptide, activates the master regulator of autophagy, a protein called Beclin 1. But developing the peptide as a potential therapeutic is hampered by its polycationic Tat sequence: this allows the peptide to gain entry into the cell, but presents toxicological issues. Joshua Kritzer, Beth Levine, and colleagues remove Tat from the equation by introducing covalent cross-linking, or “stapling”, between side chains (DOI: 10.1021/jacs.7b01698). Using thiol bis-alkylation, they make stapled versions of the Beclin-1 peptide that can enter the cell and induce autophagy both in vitro and in vivo. The work could further illuminate the molecular details of autophagy, and will be used to develop therapeutic strategies. The team’s diversity-oriented stapling approach could also be applied to help other molecules gain entry to the cell. Deirdre Lockwood, Ph.D.
Erika Gebel Berg, Ph.D.
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CLOSE ENCOUNTERS OF THE HYDROGEN KIND A team of researchers led by Peter Schreiner measure the shortest intermolecular hydrogen−hydrogen distance at only 1.567 Å (DOI: 10.1021/jacs.7b01879). Hydrogen atoms are considered “touching” at a distance of 2.4 Å, the sum of their van der Waals radii. Contact between hydrogen atoms at a distance less than 2.4 Å has previously been recorded within molecules (intramolecular contact), but this is the first observation of such a short bond between hydrogen atoms on two different molecules (intermolecular contact). The researchers observe this close bonding in the crystal structure of a dimer of sterically hindered polycyclic molecules. The ultrashort bond is measured through neutron and X-ray diffraction, and further confirmed by quantum chemical computations. The large tert-butyl groups on this molecule are responsible for significant steric hindrance, which one might think could push the two molecules apart. But in this case, these groups exert significant, stabilizing London dispersion forces (weakly attractive, temporary intermolecular forces) to compress the contact between the hydrogens. Understanding the limits of chemical bonding provides insights and improvements to molecular structure theories. Dalia Yablon, Ph.D.
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HOST−GUEST CHEMISTRY EMPLOYED IN ARRAY-BASED SENSOR FOR CANCER DIAGNOSTICS The ability to determine rapidly the geno- and phenotype of cells from a small tissue sample could lead to advances in cancer diagnostics and precision medicine. Array-based sensing is used to rapidly identify individual small-molecule and biomacromolecular analytes. Researchers are looking to these biosensing platforms to profile complex biosystems, with the goal of measuring multiple outputs in order to generate a pattern that distinguishes one cell type from another. However, traditional array-based biosensing protocols require numerous sensor units and are often limited by the need for each optical signal to be measured separately. Now, researchers led by Vincent Rotello describe a new fluorescence-based “chemical nose” method that relies on host− guest supramolecular chemistry to double the output channels of a sensor array from three to six while maintaining a single-well configuration (DOI: 10.1021/jacs.7b03657). The team demonstrates how the system can be used to provide rapid identification of cancer cell lysates, using samples of cell lysates as small as 200 ng (∼1000 cells), showing the potential of the method for microbiopsy-based cancer diagnostics. Christine Herman, Ph.D.
MODELING MECHANISM ONE QUANTUM CLUSTER AT A TIME High-resolution crystal structures, kinetic studies, and spectroscopy, among other experiments, can reveal deep insights into catalytic mechanisms, but modeling offers an approach to understanding reactions on a quantum basis. One emerging tool for modeling is the quantum chemical cluster methodology. In this Perspective, Fahmi Himo describes technical advances, recent applications, and the direction the field is likely to move in coming years (DOI: 10.1021/jacs.7b02671). The quantum cluster approach involves the modeling of a limited number of atoms (“a cluster”) in the vicinity of an enzyme’s active site. In recent years, thanks in part to the increases in computing power, the number of atoms that can be modeled has increased. To avoid multiple minima that can occur as atom counts reach the 300 mark, researchers fixed atom locations around their truncation points in the models. To improve approximations, the truncation scheme could be replaced by the introduction of energy potentials. Metalloenzymes and large protein complexes, which both catalyze complex multistep reactions, are appealing targets of the quantum cluster approach. Himo describes recent simulations of peptidyl-tRNA hydrolysis in the ribosome, phenolic acid decarboxylase, and enantioselectivity. The study of stereoselectivity with quantum clusters is particularly notable because, prior to recent advances in methodology and computing power, this was not possible. © 2017 American Chemical Society
Published: June 14, 2017 7665
DOI: 10.1021/jacs.7b05736 J. Am. Chem. Soc. 2017, 139, 7665−7665
