Drug Binding Modulates Chiral Water Structures in the DNA First Hydration Shell

Knowledge of how intermolecular interactions change hydration structures surrounding DNA will heighten understanding of DNA biology and advance drug development. However, probing changes of DNA hydration structures in response to molecular interactions and drug binding in situ under ambient conditions has remained challenging. Here, we apply a combined experimental and computational approach of chiral-selective vibrational sum frequency generation spectroscopy (chiral SFG) to probe changes of DNA hydration structures when a small-molecule drug, netropsin, binds the minor groove of DNA. Our results show that chiral SFG can detect water being displaced from the minor groove of DNA due to netropsin binding. The results show the promise of chiral SFG in offering mechanistic insights into roles of water in drug development targeting DNA. Our work demonstrates the power of chiral SFG to detect changes in first hydration shell structures of DNA and other biopolymers for investigating molecular mechanisms of biological processes.