Halogen bonds in biological molecules are short interactions between a halogen (Cl, Br, I) and an oxygen-containing group (carbonyl, hydroxyl, carboxylate, phosphate), where the X–O distance is less than or equal to the sum of their van der Waals radii. These bonds, similar to hydrogen bonds, are important for stabilizing inter- and intramolecular interactions in proteins and nucleic acids, influencing ligand binding and molecular folding. Halogen bonds can involve lone pair electrons of oxygen, nitrogen, or sulfur, or delocalized π-electrons of peptide bonds or carboxylate groups. They are now used in drug design and nanotechnology. Recent studies of biological structures reveal short halogen–oxygen interactions, such as in the enzyme aldose reductase complex with a halogenated inhibitor, where bromine–oxygen distances are significantly shorter than expected. These interactions are attributed to electrostatic effects and polarization. Halogen bonds are also found in thyroid hormones, where iodine–oxygen contacts play a role in recognition by transport proteins. Over 3,500 halogen-containing metabolites, including antibiotics, are known, and halogenation of proteins and nucleic acids can occur through oxidative processes. Quantum mechanical calculations and structural analysis of halogenated biomolecules show that halogen bonds are prevalent in biological systems, with varying geometries depending on the interacting partners. The study of halogen bonds in proteins and nucleic acids reveals that they can be directional and influence conformational equilibria. For example, in the DNA sequence d(CCAGTACbr⁵UGG), a halogen bond stabilizes a four-stranded junction. Halogen bonds can also affect the recognition of ligands and the folding of macromolecules. The study highlights the importance of halogen bonds in biological systems, suggesting they may play a role in drug design and the formation of supramolecular structures. However, the use of halogen bonds in simulations and modeling requires caution due to their unique properties. Overall, halogen bonds are a significant and versatile interaction in biological systems, influencing molecular recognition and function.Halogen bonds in biological molecules are short interactions between a halogen (Cl, Br, I) and an oxygen-containing group (carbonyl, hydroxyl, carboxylate, phosphate), where the X–O distance is less than or equal to the sum of their van der Waals radii. These bonds, similar to hydrogen bonds, are important for stabilizing inter- and intramolecular interactions in proteins and nucleic acids, influencing ligand binding and molecular folding. Halogen bonds can involve lone pair electrons of oxygen, nitrogen, or sulfur, or delocalized π-electrons of peptide bonds or carboxylate groups. They are now used in drug design and nanotechnology. Recent studies of biological structures reveal short halogen–oxygen interactions, such as in the enzyme aldose reductase complex with a halogenated inhibitor, where bromine–oxygen distances are significantly shorter than expected. These interactions are attributed to electrostatic effects and polarization. Halogen bonds are also found in thyroid hormones, where iodine–oxygen contacts play a role in recognition by transport proteins. Over 3,500 halogen-containing metabolites, including antibiotics, are known, and halogenation of proteins and nucleic acids can occur through oxidative processes. Quantum mechanical calculations and structural analysis of halogenated biomolecules show that halogen bonds are prevalent in biological systems, with varying geometries depending on the interacting partners. The study of halogen bonds in proteins and nucleic acids reveals that they can be directional and influence conformational equilibria. For example, in the DNA sequence d(CCAGTACbr⁵UGG), a halogen bond stabilizes a four-stranded junction. Halogen bonds can also affect the recognition of ligands and the folding of macromolecules. The study highlights the importance of halogen bonds in biological systems, suggesting they may play a role in drug design and the formation of supramolecular structures. However, the use of halogen bonds in simulations and modeling requires caution due to their unique properties. Overall, halogen bonds are a significant and versatile interaction in biological systems, influencing molecular recognition and function.