Schrodinger's QSite is a mixed quantum mechanics/molecular mechanics (QM/MM) program specifically targeted to biological applications. QSite is based on a pairing of Jaguar [with its fast pseudospectral implementation of density functional theory (DFT) and other ab initio methods] and Impact (a protein modeling package which employs the OPLS-AA force field). As part of Schrodinger's First Discovery suite, which also includes Glide, a high-throughput docking program, and Liaison, a ligand-receptor binding energy program, QSite has already been demonstrated to be a powerful new tool for studying the reactive chemistry of metalloenzymes. Under this Phase I proposal, QSite's capabilities will be extended by adding a synchronous transit transition state search algorithm, completing the set of parameterized QM/MM interface cuts for amino acids, and parameterizing QM/MM cuts for nucleic acids. These developments will greatly enhance QSite's robustness in characterizing the reactive chemistry of bioinorganic systems, as well as extend the range of potential applications. A proof of concept study on ligand docking to a Zn matrix metalloproteinase will also be performed, demonstrating another potential role for the program in the lead optimization process.