Molecular Determinants of Optical Modulation in ssDNA-Carbon Nanotube Biosensors: Insights from Experimental and Computational Approaches

Most traditional optical biosensors operate through molecular recognition, where ligand binding causes conformational changes that lead to optical perturbations in the emitting motif. Optical sensors developed from single-strand DNA functionalized single-walled carbon nanotubes (ssDNA-SWCNT) have started to make useful contributions to biological research. However, the mechanisms underlying their function have remained poorly understood. In this study, we used a combination of experimental and computational approaches to show that ligand binding alone is not sufficient for optical modulation in this class of synthetic biosensors. Instead, the optical response that occurs after ligand binding is highly dependent on the chemical properties of the ligands, resembling mechanisms seen in activity-based biosensors. Specifically, we show that in ssDNA-SWCNT catecholamine sensors, the optical response correlates positively with electron density on the aryl motif, even when ligand binding affinities are similar. These findings could serve as a foundation for tuning the performance of existing sensors and guiding the development of new biosensors of this class.