A recent study from Professor Elsa Yan’s lab on the disruption of water structures in DNA by drug binding has been recognized in the Most Popular 2025 Article Collections by the journal Chemical Science.
The specially curated collection highlights the exceptional research published in the journal throughout the year. Articles are selected based on a range of metrics, including citations, downloads, and online attention.
The research, led by postdoctoral fellow Ty Santiago, sheds light on the interactions between drug molecules and water molecules surrounding DNA. This understanding enhances our knowledge of the mechanisms behind drug binding to DNA, offering valuable insights for designing better drugs that target DNA molecules—such as chemotherapeutics and antibiotics.
The article has garnered recognition for demonstrating the capability of a novel spectroscopic technique to observe these critical interactions.
Water’s role in DNA is to stabilize its folding and mediate its interactions with other molecules. It acts like a protective glove over DNA grooves, which are like “handles” that drug molecules latch onto.
For a drug to “latch on,” it must strip away or change the water structures that hydrate the DNA.
Understanding these changes is key to informing better drug design.
Yet studying them requires special conditions that are not ideal. Conventional methods often involve forming crystals or using high sample concentrations, which do not closely mimic real biological environments.
In their study, the research team chose a different approach. They used an optical method known as chiral-selective vibrational sum frequency generation spectroscopy (chiral SFG), which allows for detailed probes of hydration in the original environment.
Santiago and fellow researchers used both an experimental and computational approach. They used chiral SFG to probe changes in DNA hydration structures when a small-molecule drug—netropsin—binds the minor groove of DNA. Then they performed molecular dynamics simulations to model these interactions and structural changes. Based on the models, they simulated the chiral SFG spectra for direct comparison with experiments. Through this comparison, their molecular models proved to be valid.
The study found that chiral SFG can detect water displacement from the minor groove of DNA upon netropsin binding. Additionally, chiral SFG can differentiate between weakly and strongly hydrogen-bonded water hydrating DNA. Furthermore, the researchers discovered that netropsin binding displaces strongly hydrogen-bonded water molecules from the DNA minor groove. This process is crucial for the drug’s selective binding to specific DNA sequences.
As the research has demonstrated, chiral SFG is a powerful method for understanding the role of water in drug development targeting DNA, rightly earning its place in the ‘most popular’ article collection. These findings enhance our understanding of DNA biology and could significantly advance the design of DNA-targeted drugs.
The first author of this study is Ty Santiago of Yale University. Former and current Yale co-authors are Daniel Konstantinovsky, Matthew Tremblay, Ethan Perets, Sharon Hammes-Schiffer, and Elsa Yan.
Funding for the study was provided by the National Institutes of Health and the National Science Foundation.
