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Prospects for Future Research
- The New Unified Theory of ATP Synthesis/Hydrolysis and Muscle Contraction, Its Manifold Fundamental Consequences and Mechanistic Implications and Its Applications in Health and Disease

A reader who has persisted till this point will no doubt realize that this paper has dealt with some of the most fundamental processes in biology, namely ATP synthesis, ATP hydrolysis, muscle contraction, intracellular transport, and apoptosis and cell death and that each of these fields is extremely vast and that each will have its own agenda and directions for future research. Moreover, during the last decade, the immensity of each field and the ever-accelerating pace of new advances have seen the emergence of myriad specialized sub-fields (dedicated for instance to a particular molecular motor or to a particular disease) in an attempt to keep up with the latest developments and run a manageable research program. Each of these sub-fields has its own prospects and scope for further research and it would take a lot of space to enumerate them, let alone discuss them. Hence, in the interest of brevity, of what has already been a long paper, I shall desist from doing all of the above and restrict myself to exploring prospects for research in ATP synthesis/hydrolysis and oxidative phosphorylation in the immediate future. For structural biologists in the field, solution of a highresolution structure of the complete F1FO would present the next major challenge, which will also help in understanding mechanism of the complete synthase. However, biochemists and biophysicists who are not crystallographers need not lose heart, because the vast majority of studies in this field to date have been carried out in the hydrolysis mode, and a massive amount of experimental data has been generated; in contrast, information on the mechanism of ATP synthesis by F1FO in the presence of ion gradients is extremely scarce. Hence, in the near future there is a great need to carry out biochemical and biophysical studies in the ATP synthesis mode in a bid to verify current hypotheses and to further understand crucial mechanistic issues and also give theoreticians something concrete to model in the ATP synthesis process. In turn, the torsional mechanism can catalyze this goal by serving as a guide for future experimentation. Despite several pioneering structural and single molecule studies on F1-ATPase, we still do not really know the answer to the fundamental question of how γ rotates, i.e. how force is produced by molecular interactions in the hydrolysis mode, and this aspect requires continued invesigation. Paradoxically, we can visualize force production and rotation of the c-rotor and the γ- subunit in a better way in the synthesis mode, thanks to charge geometries and models founded on the basic principles of electrostatic theory [1]. However, these models need to be extended to include rotation in ~15o/18o sub-steps resulting from the presence of two half-access channels and also to further take into account the energy storage properties of the enzyme during these sub-steps. Such analytical solutions or numerical simulations using the principles of engineering mechanics and dynamics is a worthwhile goal for the torsional mechanism, particularly because such quantification appears both attractive and feasible in the immediate future. There is also a pressing need for validation and further accurate determination of the stoichiometries of oxidative phosphorylation complexes I-V [92, 93]. Such information is essential for correct interpretation of kinetic and spectroscopic data and also for the development of structural models of supercomplex formation in mitochondria. On the redox side in oxidative phosphorylation, the central question of how electroncoupled proton translocation takes place has remained unanswered. Parallel to the new and exciting research efforts aimed at solving the molecular mechanism of ATP synthesis chronicled in this paper both comprehensively and in consummate detail, there have been a number of recent exciting experimental and theoretical attempts to elucidate the molecular mechanism of redox-linked proton translocation [94-97] but space does not permit us to delve into them here.

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