Quantitative Exploration of Molecular Machine Mechanisms

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The project will investigate the nanoscale ‘molecular machines’ that perform key tasks of biological cells, from importing nutrients to regulating compartment pH levels to synthesizing biomolecules; moreover, a number of educational efforts will accompany the research. Molecular machines have received intensive scientific scrutiny because of their importance in cell biology, but their complex functions have been difficult to characterize in a quantitative way. This project will use cutting-edge computational and data-analysis methods to make key strides toward quantification. The computational analysis will also be used to design further experiments to refine knowledge of these critical systems. Educational efforts that will supplement the research include developing an online quantitative biophysics course, developing several other online educational resources, and conducting an outreach program with high school students from economically disadvantaged backgrounds.In further detail, the research project will pursue what can be termed a systems biology approach to molecular machines, attempting to investigate a large set of mechanistic possibilities using advanced computations. It is already well-established that machines may perform more than one function, and we hypothesize that the underlying sequences of microscopic processes will prove to be heterogeneous when analyzed quantitatively. A Bayesian inference (BI) pipeline will be developed to infer quantitative models from experimental data, and the research will attempt to improve upon BI for the important class of problems with ~10 parameters. The main systems to be studied are alternating-access transporters, which use ion gradients to power small-molecule transport, and rotary ATPases, which perform the key final step in activating ATP molecules and also use ATP-derived free energy to pump ions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.