Evolution of Translation: Structure, Function, and Folding of RNA/Protein Complexes

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Evolution has given rise to all the biological processes. While its traces can be glimpsed throughout the fabric of the cell, some of its clearest markings are seen in the translation machinery (the ribosome and its associated macromolecules) that controls the critical process of protein synthesis. This machinery is present in thousands of copies in every cell and is composed of a number of RNA/protein complexes that ensure the proper production of proteins from DNA. While the individual components have been identified and characterized, an integrated picture of the process as a whole, resolved both spatially and temporally over an entire cell, is still missing. Developing such a picture is key to understanding the evolutionary history of this complex process. To extend knowledge of the function and evolution of translation to higher levels of organization and scale, this project will focus on three projects. Firstly, protein and RNA molecules form many transient complexes during the process of protein synthesis which will be studied to examine the physical nature of the binding and unbinding of these complexes. Specifically, it is not known if each binding/unbinding event is independent or if the entire chain of events is coupled. To investigate this issue, the direct migration or handoff of a tRNA molecule from the enzyme that charges it with an amino acid to the elongation factor that takes it to the ribosome will be modeled. The simulation results will be compared to studies carried out in collaboration with experimental groups. Secondly, the role of ribosomal signatures in the folding and binding of ribosomal proteins and RNA will be examined computationally with a variety of methods. An understanding of how signatures unique to a domain of life affect ribosome assembly will provide insight into how the assembly process has evolved since the divergence of the three primary organismal lineages. Thirdly, a new computational approach will be developed to study the kinetics of the translation process in the crowded environment of the cell. These 3D lattice simulations take advantage of recent advances in GPU computing to enable simulations of the translation process in a coarse grained bacterial cell under in vivo conditions on the time scale of the cell cycle. Hypotheses about how the process of translation occurs at a cellular scale will be tested. All of the visualization, simulation, and analysis tools developed to study macromolecular RNA/protein assemblies involved in translation will be made available through the MultiSeq extension to the popular visualization program VMD that is freely distributed. These techniques will also be incorporated into an existing series of tutorials used in teaching computational biology. The tutorials are available online, through workshops periodically given across the country, and in the CHEM/BIOP470 Computational Chemical Biology course taught at the University of Illinois. The PI's research group will continue to participate in the NSF sponsored Graduate Teaching Fellows program that helps high school teachers prepare state-of-the-art scientific curricula for their classrooms. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division.