What is it about?
Since the late 1800’s, Mendeleev's periodic table has helped chemists predict how elements behave. This study by Walker, et al. (1), shows that a quantum mechanical effect allows halogens (electron-rich elements on the far right-hand side of the periodic table) to behave like and substitute for the function of a magnesium (a positively charged metal ion on the far left-hand side) in enzyme catalysis. In this work, an amino acid in the active site of a DNA cutting enzyme (an endonuclease) that holds a catalytic magnesium is replaced by an unnatural halogenated amino acid. This halogen interacts with the DNA in a way that mimics how the magnesium ion makes the DNA backbone susceptible to cleavage by water. One can ask, how can a halogen mimic the catalytic function of a magnesium? Quantum mechanical theory tells us that pairing the electron of an atom with that of a second atom forms a chemical bond, but in doing so, the electrons around that atom is no longer evenly distributed (2). Forming this chemical bond results in a “hole” of depleted electrons and thus a positive charge on the tip of the atom opposite that bond. This quantum effect applies to all chemically bonded atoms and, for halogens, this positive “hole” mimics the positive charge of the metal ion to form what is now called a halogen bond to the DNA. In 2004, halogen bonds were found to help recognition and binding of halogenated inhibitors and drugs by proteins (3), which now explains the important role of this class of elements in drug discovery and design. This current work by Walker, et al., extends the properties of halogen bonds to now functionally substituting for magnesium and potentially other metals in enzymes. 1. Walker, M.G., Mendez, C.G., Ho, A.N., Czarny, R.S., Rappé, A.K., Ho, P.S. Proc Natl Acad Sci, USA., 122 (14) e2500099122 (2025) 2. Clark, T., Hennemann, M. , Murray, J. S. , Politzer, P. J. Mol. Model. 13, 291–296 (2007). 3. P. Auffinger, F. A. Hays, E. Westhof, P. S. Ho, Halogen bonds in biological molecules. Proc. Natl. Acad. Sci. U.S.A. 101, 16789–16794 (2004)
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Why is it important?
Halogen bonding is added as a new tool to the molecular synthetic biology toolbox for designing and engineering new enzymes using a chemical mechanism not currently found in nature. In the process, the study demonstrates how quantum mechanics challenges the fundamental concept that the chemical properties of the elements are so neatly cataloged into a structured periodic table.
Perspectives
There are generally two ways to approach scientific research: data driven discovery science and exploratory inventive science. Generative artificial intelligence (AI) is quickly being adopted to facilitate the discovery of new theories and principles based on the interpretation of large sets of experimental and/or computational data. The primary hypothesis of this study by Walker, et al. draws from no prior database, while connecting two disconnected ideas—halogen bonding and metal catalyzed DNA processing enzymes—and, thus, could not have been “imagined” by current AI algorithms. Expanding AI into more conceptual, less structured realms of science will require a new, less data driven model, perhaps even beyond the yet to be fully realized artificial general intelligence (AGI) platforms.
Pui Ho
Colorado State University System
Read the Original
This page is a summary of: Design of a halogen bond catalyzed DNA endonuclease, Proceedings of the National Academy of Sciences, April 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2500099122.
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