CAREER: The origins of codon translation rates and their consequences for nascent protein behavior

Proteins are made up of amino acid building blocks and are responsible for performing most of the jobs in the cells of all biological organisms. An emerging paradigm in the field of protein biophysics is that the rate that the protein is synthesized or translated on the ribosome controls the ultimate fate of the protein, such as whether the protein correctly folds, misfolds, aggregates or dimerizes, is moved to a specific cellular location, or is processed in such a way as to modify its function. The goal of this project is to use computer simulations and theory to understand the influence of rates of protein synthesis on nascent protein behavior including protein folding and dimerization during translation. Through this project, grade-school and high-school women and minority students will be encouraged to pursue STEM educations by exposing them to cutting-edge scientific research in computational biophysics. This project will also expose graduate students to an international collaboration, which will help them develop an international-network of scientific colleagues. Pulling forces on the nascent protein chain, generated by the co-translational folding of a domain, have recently been shown to influence codon translation rates to overcome stalling sequences. The hypothesis to be tested is that the magnitude of the tensile force experienced by a nascent chain during protein synthesis is influenced by a number of factors, including the stability of the folded domain and its size. In the first objective, this hypothesis will be tested by using molecular simulations at different resolutions to determine the molecular mechanism by which tension modulates codon translation rates. In the second objective, the role of codon translation rates in coordinating co-translational folding will be investigated to evaluate the predominant paradigm in the co-translational protein folding field that only slow-translating codons can maximize co-translational folding. This goal will be accomplished by creating a new coarse-grained protein folding model that allows for misfolding and then test the 'Fast-translating Codon' hypothesis that posits that fast-translating codons can maximize co-translational folding by speeding through the synthesis of misfolding-prone segments thereby increasing the flux into the native state. In the final objective, the investigator will explore the observation that changes in codon translation rates can alter a protein's function but not necessarily its solubility, suggesting that structural changes in the nascent protein must be modest because otherwise aggregation would likely occur. How extensive these structural rearrangements may be will be investigated by simulating the synthesis of proteins that heterodimerize and by calculating how their binding affinity changes as codon translation rates are altered. This work will provide significant insights into folding and behavior of nascent proteins while challenging the current paradigm.