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

蛋白质由氨基酸组成，负责执行所有生物有机体细胞中的大部分工作。蛋白质生物物理学领域中的一个新兴范例是蛋白质在核糖体上合成或翻译的速率控制蛋白质的最终命运，例如蛋白质是否正确折叠、错误折叠、聚集或二聚化，是否被移动到特定的细胞位置，或者是否以改变其功能的方式被加工。 该项目的目标是使用计算机模拟和理论来了解蛋白质合成速率对新生蛋白质行为的影响，包括翻译过程中的蛋白质折叠和二聚化。通过这个项目，将鼓励小学和高中妇女和少数民族学生通过接触计算生物物理学的前沿科学研究，接受STEM教育。该项目还将使研究生接触到国际合作，这将有助于他们建立一个科学同事的国际网络。由结构域的共翻译折叠产生的新生蛋白质链上的拉力最近已被证明影响密码子翻译速率以克服停滞序列。要测试的假设是，蛋白质合成过程中新生链所经历的张力的大小受许多因素的影响，包括折叠结构域的稳定性及其大小。在第一个目标中，将通过使用不同分辨率的分子模拟来测试这一假设，以确定张力调节密码子翻译速率的分子机制。在第二个目标中，将研究密码子翻译速率在协调共翻译折叠中的作用，以评估在共翻译蛋白质折叠领域中的主导范式，即只有慢翻译密码子才能最大化共翻译折叠。这一目标将通过创建一个新的粗粒度蛋白质折叠模型来实现，该模型允许错误折叠，然后测试“快速翻译密码子”假设，该假设假定快速翻译密码子可以通过加速合成易发生错误折叠的片段来最大化共翻译折叠，从而增加进入天然状态的通量。在最终目标中，研究人员将探索观察到密码子翻译速率的变化可以改变蛋白质的功能，但不一定改变其溶解度，这表明新生蛋白质的结构变化必须是适度的，因为否则可能会发生聚集。如何广泛的这些结构重排可能是将研究通过模拟异二聚化的蛋白质的合成，并通过计算它们的结合亲和力如何改变密码子翻译速率的改变。这项工作将为新生蛋白质的折叠和行为提供重要的见解，同时挑战当前的范式。

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.