Self-assembling macromolecular machines such as the ribosome and spliceosome are central tofundamental 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 andfunctional conformation is necessary to achieving a predictive understanding of cellular processes. The largenumber of components that make up a macromolecular machine result in a highly complex assemblyreaction. Recent developments in the throughput and variety of experimental approaches that probe thesereactions provide a cornucopia of information. Integrating these data and building consistent descriptions ofthe assembly process requires the development of sophisticated algorithms that integrate multi-scale dataand leverage the ever increasing power of large distributed computing grids. This proposal outlines theextension and application of novel algorithms that create quantitative and predictive structural and dynamicdescriptions of molecular assembly processes based on kinetic measurements of the reaction. Thesealgorithmic developments, in conjunction with the acquisition of large data sets on the assembly reaction ofthe 30S ribosomal subunit, will be used to create a highly detailed quantitative description of the assemblyreaction of this critical molecular machine. The description will greatly deepen our understanding ofmolecular assembly, as it will predict the number and complexity of the possible assembly pathways, as wellas 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 differentcomponents. 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, inhibitand/or modify the function of the machine. One direct application of this work is the development of novelantibiotics, as the bacterial ribosome is a major pharmaceutical target. Furthermore, a detailed blueprint ofthe assembly process will significantly improve our ability to engineer novel molecular machines with entirelynew function.
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