The union of transition metal catalysis with native biochemistry presents a powerful opportunity to perform abiotic reactions within complex biological systems. However, several chemical compatibility challenges associated with incorporating reactive metal centers into complex biological environments have hindered efforts in this area, despite the many opportunities it may present. More challenging than chemical compatibility is biocommunicative transition metal catalysis, where the reactivity of the metal species is regulated by native biological stimuli, akin to natural biocatalytic processes. This dissertation describes the discovery of Au(I)-bound metal-mediated base pairs (MMBPs) in pyrimidine mismatches. Additionally, the application of these Au(I)-DNA complexes as catalysts that are dependent on genetic information was shown. These Au(I)-DNA catalysts form fluorescent product in response to nucleic acid fragments and can be used to detect nucleic acids in complex biological matrices. Chapter One is a perspective on transition metal bound to RNA and DNA sequences. These complexes often possess nuclease-type activity in natural biological systems. However, there are some examples of researchers creating abiotic metalallo-nucleic acid complexes that are asymmetric catalysts, that exhibit sequence rate enhancing ligands, or in a few rare examples, are activated through addition of a specific sequence. Chapter Two details experimental and computational studies of Au(I) metal-mediated base pairs with all three pyrimidine mismatches. Au(I) is incorporated into DNA duplex and hairpin structures containing a C–C, C–T, and T–T mismatch leading increases in thermal stability, changes in circular dichroism, and mass adducts through mass spectrometry. The stable complexes formed through the addition of (Me2S)AuCl to these mismatches can be used in further applications in nanotechnology and biocatalysis. Chapter Three describes the activity of a Au(I)-DNA catalyst formed through a C–Au(I)–T metal-mediated base pair. This catalyst is composed of a DNA hairpin structure with a toehold sequence, to aid in hybridization, and a C–T mismatch in the stem. Once the Au(I) precursor is added, an inactive catalyst is formed. Only through hybridization does this catalyst become active, catalyzing the formation of a fluorescent BODIPY molecule through a Au(I)-catalyzed hydroamination reaction. This catalyst become active when hybridized to DNA or RNA complement and exhibits sequence selectivity for the nucleic acid analyte. Chapter Four outline the development of a Au(I)-DNA catalyst that exhibits turnover, unlike the previous catalyst system (Chapter Three). This catalyst, formed through a C–Au(I)–C metal-mediated base pair, catalyzes the formation of a fluorescent coumarin derivative through a Au(I)-catalyzed hydroarylation. The Au(I)-DNA catalyst or Au(I)-CAP (chemocatalytic amplification probe) with substrate, leads to significant increases in fluorescence, even at low nM concentrations of catalyst. This Au(I)-CAP system outperforms standard molecular beacon technology and works in complex biological systems, such as cell lysates and E. coli whole cells, leading to a fluorescent response. Chapter Five describes the use of a Au(I)-CAP that hybridizes to SARS-CoV-2 related nucleic acid fragments. Hairpins were designed such that they hybridize to either the viral RNA or viral cDNA of the N gene of the SARS-CoV-2 genome. These catalysts form a fluorescent coumarin product in response to the viral genetic information leading to detection levels in the low fM range. In addition, this can be paired with a nucleic acid amplification technique to detect less than 1 copy/ul of viral RNA or DNA. Finally, direct detection of viral RNA from heat-inactived virus in human saliva was achievable in this system.