This is a copy of the slides presented at the meeting but not formally written up for the volume.

Nanoscale interfaces to proteins have been achieved for a variety of applications, in the form of electrodes to measure conductivity, for sensing on cantilevers or fluorescent quantum dots, or nanoparticles that can be used as reporters in receptor-ligand binding assays. One prevailing requirement is that the biological function of the protein is maintained when linked to nanoscale systems. Due to the structure-function relationship of proteins, the protein must maintain its folded structure. We covalently link cytochrome c and Ribonuclease S to Au or magnetic nanoparticles (NPs) and study the interface, with the goal of constructing design rules that govern the interaction. In both cases we devise methods to achieve linkage of a nanoparticle to the protein on a specific amino acid, in addition to chemical treatments that minimize non-specific adsorption. The protein linked to the nanoparticles is biophysically characterized. Protein secondary structure was quantified by circular dichroism spectroscopy (CD). From these measurements we determine that electrostatic forces dominate the NP-protein interaction and minimization of these results in folded proteins with minimal non-specific adsorption. For Ribonuclease S, these findings are integrated with measurements of enzymatic activity and binding constants KM to yield a picture of the how the protein interaction with the NP affects its binding to the substrate and activity. Experiments in which the NP labeling position, NP ligand, size, and material (Au, Fe3O4, CoFe2O4) are systematically varied will be discussed.