The free energy landscapes governing the function of complex biomolecular machines

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Complex macromolecular assemblies of proteins, nucleic acids and carbohydrates consume energy in order to perform specific biological functions. The concerted action of these "molecular machines" underlies all the activities of the living cell. Therefore, a better understanding of this machinery will allow us to answer fundamental questions about the biology of all organisms. The proteins associated with biological membranes are particularly remarkable. Proteins such as ion channels, transporters, pumps, receptors, kinases, and phosphatases play an essential role in controlling the bidirectional flow of material and information across the biological membrane, and as such, they are truly devices able to accomplish complex tasks. This project will use an extremely large allocation of computer time on the largest NSF-supported HPC system, Blue Waters, to gain a deep mechanistic perspective of protein function, linking structure to dynamics, by characterizing the free energy landscapes that govern key functional processes in these systems. Deliverables from the project include not only fundamental scientific insights about the systems under investigation, but also computational tools for investigating biomolecules, and the free distribution of software and extended computer scripts. All development work (parameters, software computer programs and scripts) will be made publicly available to the academic community.Some proteins can act as an electric pump, consuming ATP to carry charged ions against their electrochemical potential gradient, while some, like ion channels, simply allow selected ions to diffuse passively. Strong electrostatic interactions involving ions or charged residues are often implicated in the function of these systems. For example, at the heart of the molecular mechanism of the ATP-driven ionic pumps are fundamental processes of ion diffusion and binding to selective binding sites in the core of the protein. This project will use Blue Waters to investigate the selective ion binding processes in one important ATP-driven pumps: the Na+/K+-ATPase. It will also study the factors controlling the stability of the C-type inactivated state of the selectivity filter of the csA K+ channel, a non-conducting state of K+ channels of great physiological implications. In the proposed work, ATP-driven ion pumps, K+ channels, and Src tyrosine kinases will be studied within a unified computational perspective provided by free energy landscapes.