Detection of molecular interactions is critical for understanding many biological processes, for detecting disease biomarkers, and for screening drug candidates. To date the most widely used detection technique uses fluorescence dyes. While useful, the approach can be problematic when applied to the detection of small molecules, because the dye molecules may significantly alter the binding activities of the small molecules. Label-free detection techniques have been developed, but they largely rely on the detection of the mass of a molecule, which are difficult for small molecules. Small molecules are the most popular form of drugs, and play important roles in many biological processes, including post-translational modification of proteins, metabolic and cellular signaling processes. A capability to detect small molecules will have large impacts on the understanding of these processes, detecting of diseases, and discovery of drugs.

 We show that molecular interactions with membrane proteins induce mechanical deformation in cellular membrane, and real-time monitoring of the deformation allows quantitative analysis of membrane protein binding kinetics. This new strategy provides mechanical amplification to small binding signals, which, together with a differential optical detection algorithm to track cell deformation with 0.5 nm accuracy, make it possible to detect small molecule interactions with membrane proteins. This capability also allows study of heterogeneous nature of cells by analyzing the binding kinetics variability between different cells, and different regions of a single cell.