Self-assembling macromolecular machines such as the ribosome and spliceosome are central to fundamental cellular processes including transcription, mRNA processing, translation, and DNA replication. Creating a quantitative and predictive description of the sequence of steps leading to their assembled and functional conformation is necessary to achieving a predictive understanding of cellular processes. The large number of components that make up a macromolecular machine result in a highly complex assembly reaction. Recent developments in the throughput and variety of experimental approaches that probe these reactions provide a cornucopia of information. Integrating these data and building consistent descriptions of the assembly process requires the development of sophisticated algorithms that integrate multi-scale data and leverage the ever increasing power of large distributed computing grids. This proposal outlines the extension and application of novel algorithms that create quantitative and predictive structural and dynamic descriptions of molecular assembly processes based on kinetic measurements of the reaction. These algorithmic developments, in conjunction with the acquisition of large data sets on the assembly reaction of the 30S ribosomal subunit, will be used to create a highly detailed quantitative description of the assembly reaction of this critical molecular machine. The description will greatly deepen our understanding of molecular assembly, as it will predict the number and complexity of the possible assembly pathways, as well as establish the degree of cooperativity between the RNA and protein components of the machine. Public Health Statement: Like all machines capable of carrying out complex tasks, the ribosome is comprised of many different components. By understanding how these components come together to make a fully functional molecule, we are effectively reverse engineering the machine. This new understanding will help us enhance, inhibit and/or modify the function of the machine. One direct application of this work is the development of novel antibiotics, as the bacterial ribosome is a major pharmaceutical target. Furthermore, a detailed blueprint of the assembly process will significantly improve our ability to engineer novel molecular machines with entirely new function.
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