Cellular activities are mediated by proteins, which often undergo conformational changes to regulate binding and enzymatic activities that direct signaling pathways. Hence, it is important to develop and apply tools to characterize dynamic changes in protein conformation. A variety of approaches are available, including those based on NMR, 1 FRET, 2 and plasmonics. 3,4 Plasmonic approaches are particularly useful because they provide an intense signal that does not bleach and allow non-destructive measurement over long periods of time. In addition to acting as probes of molecular interactions, plasmonic devices have significant potential as nanoscale optical switches, waveguides, light sources, microscopes and lithographic tools. 3,4 Herein, we demonstrate a plasmonic switching device based on the calcium-induced conformational changes of calmodulin. The extinction maximum (λ max ) of a Localized Surface Plasmon Resonance (LSPR) sensor functionalized with calmodulin reversibly shifts by 2-3 nm in response to changes in Ca 2+ concentration, creating a unique on/off switch and providing information about the dynamics and structure of the protein. A high resolution (HR)-LSPR spectrometer with a wavelength resolution (3Ï) of 1.5Ă10 -2 nm was used to detect the calciummodulated wavelength shifts (supporting information).The LSPR is a unique nanoscale phenomenon that gives rise to an intense extinction and scattering spectrum in noble metal nanoparticles that is highly dependent on the local refractive index at the nanoparticle surface. Biomolecule adsorption to a nanoparticle alters the local refractive index, causing shifts in the extinction maximum (λ max ). The magnitude and direction of these shifts provide detailed information about the packing density of the adsorbed species. 5 LSPR sensors can be used to characterize and detect a wide variety of biological events, including DNA hybridization, 6 carbohydrate-protein binding, 7 and antigen-antibody interactions. 8,9 A commercially established technology based on propagating SPR in thin Au films can sense changes in refractive index up to 1 ÎŒm away from the sensor surface. Such SPR sensors have been used to detect protein conformational changes due to denaturation. 10 11, However, the relatively large sensing region of propagating SPR sensors gives rise to interference from bulk refractive index changes. In contrast, the LSPR sensing region in Ag nanoparticles is confined to a thin (25 -30 nm) shell around the nanoparticle. 12 As a result, LSPR sensors possess 40-fold greater spatial resolution normal to the sensor surface, allowing improved detection of low molecular weight binding events. Monitoring LSPR changes in real-time provides information about the dynamics of binding events and protein folding, with much less interference from bulk refractive index changes.vanduyne@northwestern.edu Supporting Information Available: Experimental details and data not shown in the manuscript are available free of charge via the internet at http://pubs.acs.org. To immobiliz...