Proteins are biopolymers that perform a myriad of functions in living cells. These functions are determined by each protein's three-dimensional structure. Current knowledge of protein folding principles provides a partial understanding of the thermodynamic factors that drive protein structure, folding, and stability, sufficient to allow proteins to be treated as templates for design and engineering. This project used protein engineering to explore protein structure and folding mediated by interactions with metal ions. As a proof of principle, experiments were undertaken that aimed to re-engineer staphylococcal nuclease to contain a metal ion-dependent switch that exhibits a loss of structure in the absence of a specific metal ion but recovers its native fold in the presence of that ion. Spectroscopic methods were used to monitor structural changes between the metal-free and the metal-bound protein. Changes in the protein's amino acid sequence were introduced systematically to create nickel (II) binding sites based on a naturally occurring high-affinity nickel site. The site was comprised of four amino acid side chains that coordinated the metal ion. Several iterations of candidate proteins, each containing a putative nickel binding site comprised of 2-4 residues, and of reference proteins lacking this site were designed, produced, and characterized spectroscopically. From each of the protein iterations, information was obtained about the refolding process, including the effects of steric constraints, protein oligomerization, and protein thermodynamics. Proteins with fewer substitutions were more effective at maintaining their structure due to a reduced thermodynamic penalty.