The translocation of protons in biomolecular systems is a phenomenon of fundamental importance to such biological processes as ATP synthesis, enzyme catalysis, the maintenance of pH gradients, proton pumping, and bioenergetics. From the computational point of view the modeling of proton translocation represents a particularly difficult challenge most notably because of the many complex interactions involved, the fact that bonding topologies are continually evolving due to the Grotthuss proton shutting between water molecules and also possibly with other molecular groups, the interplay of charge migration via proton shuttling and classical ion diffusion, and the overall structural complexity of the target biomolecular systems. In most instances, the primary question is the way in which Nature utilizes the proton shuttling characteristics of hydrogen bonded water chains within proteins, as well as how specific molecular groups within the protein participate in the proton translocation process via electrostatic interactions and possibly even via direct participation in the proton shuttling mechanism itself. In this project the continued development and application of a unique and powerful computer simulation methodology is described for the study of proton translocation in several key classes of proton translocating biomolecular systems, including channels (M2 proton channels of influenza A and B, mutated aquaporin channels, and chloride/proton antiporter channels), enzymes (carbonic anhydrase), and proton pumps (cytochrome c oxidase). The overall research plan is made possible by a novel Molecular Dynamics simulation approach that allows for the study of explicit proton transport through water molecules and ionizable molecular groups in hydrogen bonded networks. A primary target in the research will be to reveal the underlying microscopic biomolecular interactions which influence proton translocation in the above mentioned systems, as well as the way in which structural and chemical modifications of the proteins can affect this important property. These studies will be carried out in collaboration with several key experimentalists, while adding a new dimension to the field of biomolecular computer simulation as a whole. 1The project concerns computer simulation studies of proton translocation in several key biomolecular systems. Proton translocation is important to understanding numerous aspects of human health, including influenza viral replication, neurodegeneration, glaucoma, metabolism, and aging.