Scientists Develop First Artificial DNA Base Pair Using Halogen Bonds

Professor Stephanie Kath Schorr and her research team at the University of Cologne have reported the first artificial DNA base pair held together not by hydrogen bonds, which stabilize natural DNA, but by halogen bonds. The work, published in the Journal of the American Chemical Society, demonstrates that the molecular framework of DNA can be engineered to rely on a different intermolecular interaction while remaining compatible with enzymatic replication. The findings expand the conceptual boundaries of synthetic genetics and raise new questions about the chemical flexibility of the genetic molecule.

Dörrenhaus, R., Wagner, P. K., Wilczek, L., Lüggert, S., Behn, T. A., Breugst, M., & Kath-Schorr, S. (2026). Investigating Halogen Bonds as Pairing Force in an Artificial DNA Base Pair. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.5c23044

In natural DNA, adenine pairs with thymine and guanine pairs with cytosine through hydrogen bonds. These directional electrostatic interactions ensure that the double helix maintains a consistent geometry and that genetic information is copied accurately during replication. For decades, hydrogen bonding has been considered a defining feature of base pairing. The Cologne group set out to test whether that assumption is chemically necessary or whether alternative forces could be engineered to perform the same structural and informational role.

Professor Stephanie Kath Schorr and her research team at the University of Cologne stated,

“DNA does not rely exclusively on the known chemical principle. Our results expand the genetic alphabet and deepen our understanding of how flexible the molecule of life truly is.”

Halogen bonds arise when a halogen atom such as iodine forms a directional attraction with an electron rich partner. Although halogen bonding has been studied extensively in supramolecular chemistry and materials science, it has not previously been used as the central pairing force within a functional DNA base pair. The team designed synthetic nucleobases containing iodine atoms positioned to create highly directional halogen bond interactions. The objective was to mimic the spatial precision required within the double helix while substituting the underlying chemical interaction.

The work began with computational modeling. Using molecular simulations, the researchers evaluated how the artificial nucleobases would orient within the DNA helix and whether halogen bonding could provide sufficient stability without distorting the overall structure. Geometry was critical. DNA polymerases recognize shape and spacing as much as they recognize chemistry. Any deviation in bond angles or base stacking could prevent replication.

Once theoretical models indicated viable configurations, the team synthesized the modified nucleotides in the laboratory. They then incorporated them into short DNA strands to test whether the artificial bases selectively recognized each other. Biochemical assays showed that the synthetic bases formed stable and specific pairs when placed opposite each other in a DNA duplex. Analytical techniques confirmed that the halogen bond interactions were responsible for the pairing behavior rather than residual hydrogen bonding.

A key question in artificial genetics is whether a synthetic base pair can function within the machinery of life rather than only in isolated chemical systems. DNA polymerases act as cellular copying enzymes, reading template strands and incorporating complementary nucleotides. Many earlier artificial base pairs have required engineered polymerases or highly controlled laboratory conditions to achieve replication.

In this study, the researchers demonstrated that a naturally occurring DNA polymerase could accept the halogen bonding nucleotides and incorporate them into a growing DNA strand. Primer extension experiments confirmed successful replication across templates containing the artificial base. The enzyme recognized the modified nucleotides and extended the strand without immediate rejection, indicating that the overall geometry of the pair was compatible with biological copying mechanisms.

This enzymatic acceptance is significant because it suggests that hydrogen bonding is not the only viable strategy for encoding complementary information within DNA. The double helix appears to tolerate more chemical diversity than previously assumed, provided that the steric and spatial parameters remain within functional limits.

The research builds upon decades of efforts to expand the genetic alphabet. Scientists have previously developed unnatural base pairs based on alternative hydrogen bonding schemes and hydrophobic interactions. Some of these systems have even been introduced into semi synthetic organisms capable of storing additional genetic information. However, those systems typically preserved hydrogen bonding as a central design principle. The Cologne team’s approach represents a conceptual shift by replacing hydrogen bonding entirely as the primary pairing interaction.

Beyond expanding the alphabet of DNA, the study provides insight into molecular evolution. Hydrogen bonds dominate natural base pairing, but this may reflect evolutionary selection rather than chemical exclusivity. By demonstrating that halogen bonds can sustain duplex stability and enzymatic processing, the researchers show that DNA’s architecture is more adaptable than once believed.

From an engineering standpoint, the implications extend into synthetic biology and molecular design. Increasing the number of functional base pairs could expand the information density of DNA constructs used in biotechnology. Additional chemical functionalities may enable new labeling strategies, improved diagnostic probes, or novel therapeutic nucleic acids with altered stability profiles.

Artificial bases that rely on halogen bonding might also influence the physical properties of DNA assemblies. Changes in intermolecular forces can affect duplex melting temperature, stacking interactions, and resistance to enzymatic degradation. Understanding these effects could inform the design of nucleic acid materials for nanotechnology or gene delivery systems.

Despite these prospects, the research remains at an early stage. The experiments were conducted in controlled laboratory conditions, and further work will be required to assess replication fidelity over multiple cycles, structural stability in complex biological environments, and long term compatibility with cellular processes. It will also be necessary to determine whether such artificial bases can be integrated into living systems without unintended consequences.

The study nevertheless underscores a broader principle in molecular engineering. Biological macromolecules are not constrained to a single chemical solution. The double helix can accommodate alternative interactions if they preserve geometry, spacing, and recognition patterns. By carefully designing new building blocks that respect these constraints, researchers can explore chemical territory beyond that selected by natural evolution.

Professor Kath Schorr has described the findings as evidence that DNA does not rely exclusively on a single chemical principle. The work reframes the double helix not as a fixed chemical artifact but as a modular platform capable of supporting alternative bonding logic. For engineers working at the interface of chemistry and biology, this flexibility opens opportunities to rethink how genetic systems are constructed and manipulated.

As research into expanded genetic systems progresses, halogen bonding may become part of a broader toolkit for reengineering nucleic acids. The current work demonstrates that with precise modeling, careful synthesis, and rigorous biochemical testing, even fundamental features of biology can be redesigned. The achievement lies not only in introducing a new base pair but in revealing that the molecular rules of life are more adaptable than once assumed.