A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design

Of the manifold concepts in drug discovery and design, covalent drugs have re-emerged as one of the most promising over the past 20-or so years. All such drugs harness the ability of a covalent bond to drive an interaction between a target biomolecule, typically a protein, and a small molecule. Formation of a covalent bond necessarily prolongs target engagement, opening avenues to targeting shallower binding sites, protein complexes, and other difficult to drug manifolds, amongst other virtues. This opinion piece discusses frameworks around which to develop covalent drugs. Our argument, based on results from our research program on natural electrophile signaling, is that targeting specific residues innately involved in native signaling programs are ideally poised to be targeted by covalent drugs. We outline ways to identify electrophile-sensing residues, and discuss how studying ramifications of innate signaling by endogenous molecules can provide a means to predict drug mechanism and function and assess on- versus off-target behaviors.

Formation of the BeH+ and BeD+ Molecules in Be+ + H/D Collisions Through Radiative Association

Cross sections and rate coefficients for the formation of BeH+ and BeD+ molecules in Be+ + H/D collisions through radiative association are calculated using quantum mechanical perturbation theory and Breit-Wigner theory. The local thermodynamic equilibrium limit of the molecule formation is also studied, since the process is also relevant in environments with high-density and/or strong radiation fields. The obtained rate coefficients may facilitate the kinetic modelling of BeH+/BeD+ production in astrochemical environments as well as the corrosion chemistry of thermonuclear fusion reactors.

Interstellar and Intergalactic Medium

This concise textbook, the first volume in the Ohio State Astrophysics Series, covers all aspects of the interstellar and intergalactic medium for graduate students and advanced undergraduates. This series aims to impart the essential knowledge on a topic that every astrophysics graduate student should know, without going into encyclopedic depth. This text includes a full discussion of the circumgalactic medium, which bridges the space between the interstellar and intergalactic gas, and the hot intracluster gas that fills clusters of galaxies. Its breadth of coverage is innovative, as most current textbooks treat the interstellar medium in isolation. The authors emphasise an order-of-magnitude understanding of the physical processes that heat and cool the low-density gas in the universe, as well as the processes of ionization, recombination, and molecule formation. Problems at the end of each chapter are supplemented by online projects, data sets and other resources.

The Basics of Covalent Bonding in Terms of Energy and Dynamics

We address the paradoxical fact that the concept of a covalent bond, a cornerstone of chemistry which is well resolved computationally by the methods of quantum chemistry, is still the subject of debate, disagreement, and ignorance with respect to its physical origin. Our aim here is to unify two seemingly different explanations: one in terms of energy, the other dynamics. We summarize the mechanistic bonding models and the debate over the last 100 years, with specific applications to the simplest molecules: H2+ and H2. In particular, we focus on the bonding analysis of Hellmann (1933) that was brought into modern form by Ruedenberg (from 1962 on). We and many others have helped verify the validity of the Hellmann–Ruedenberg proposal that a decrease in kinetic energy associated with interatomic delocalization of electron motion is the key to covalent bonding but contrary views, confusion or lack of understanding still abound. In order to resolve this impasse we show that quantum mechanics affords us a complementary dynamical perspective on the bonding mechanism, which agrees with that of Hellmann and Ruedenberg, while providing a direct and unifying view of atomic reactivity, molecule formation and the basic role of the kinetic energy, as well as the important but secondary role of electrostatics, in covalent bonding.

Studies on the Properties of the Sporulation Specific Protein Dit1 and Its Product Formyl Tyrosine

The dityrosine layer is a unique structure present in the spore wall of the budding yeast Saccharomyces cerevisiae. The primary constituent of this layer is bisformyl dityrosine. A sporulation-specific protein, Dit1 is localized in the spore cytosol and produces a precursor of bisformyl dityrosine. Although Dit1 is similar to isocyanide synthases, the loss of Dit1 is not rescued by heterologous expression of the Pseudomonas aeruginosa isocyanide synthase, PvcA, indicating that Dit1 does not mediate isocyanidation. The product of Dit1 is most likely formyl tyrosine. Dit1 can produce its product when it is expressed in vegetative cells; however, formyl tyrosine was not detected in the crude cell lysate. We reasoned that formyl tyrosine is unstable and reacts with some molecule to form formyl tyrosine-containing molecules in the cell lysate. In support of this hypothesis, formyl tyrosine was detected when the lysate was hydrolyzed with a mild acid. The same property was also found for bisformyl dityrosine. Bisformyl dityrosine molecules assemble to form the dityrosine layer by an unknown mechanism. Given that bisformyl dityrosine can be released from the spore wall by mild hydrolysis, the process of formyl tyrosine-containing molecule formation may resemble the assembly of the dityrosine layer.