Motor proteins are fascinating molecular machines powered by ATP. With recent progress in experimental techniques such as single molecular spectroscopy, some "secrets" of those "nano- biomachines" are being revealed. However, a detailed mechanism for the chemomechnical coupling at atomic resolution is still lacking. What is the nature of coupling between the chemical step (ATP binding or hydrolysis) and the subsequent conformational change? What are the critical residues that regulate such a coupling, and how do they achieve that? Answering those questions is of great significance because it will not only yield novel insights into the "structure-function" relationship in biological macromolecules but can also provide clues to engineering efficient artificial systems.

ATP synthase is a remarkable and experimentally well studied example of a molecular motor. Its biological function is to synthesize the fuel of life---ATP. Therefore, understanding its working mechanism is of central importance in bioenergetics. Through a large body of biochemical, structural and biophysical studies, the overall mechanism of this remarkable machine is available in outline form, but important questions of the mechanistic details at the atomic level remain to be answered. For instance, according to the "binding change" mechanism, the catalytic b domain switch among three different conformations, which play different roles in ATP synthesis or in motor functions on ATP hydrolysis. However, the precise structural and energetical elements of the coupling between conformation and ATP hydrolysis/synthesis is not understood. The conformational changes of the b subunits are proposed to be driven by the rotation of the central g stalk, which in turn is coupled to the conformational change in the transmembrane domain induced by proton translocation across the membrane, i.e., the proton motive force. Elegant single molecular spectroscopy and NMR experiments have verified those coupled motions. It was not possible, however, to extract detailed pathways at atomic resolution. Without the transmembrane domain, ATP synthase becomes a reversed engine, i.e. it hydrolyzes ATP. Single molecular measurements suggest that this bio-engine is highly efficient, nearly 100%, in converting chemical (hydrolysis) free energy into mechanical work. A convincing structural rationalization for such a high efficiency is not available, although there are proposals based on phenomenological studies. With the most recent structural information on ATP synthase, calculations on the energetics for the chemical steps and pathways for the conformational transitions can complement experimental work and yield detailed views on various aspects of this wonderful machine at atomic resolution.