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

职业：密码子翻译率的起源及其对新生蛋白质行为的影响

• 批准号: 1553291
• 负责人: Edward O'Brien
• 金额: $ 89万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1553291&HistoricalAwards=false
• 关键词: CAREER; origins; codon; translation; rates

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.

蛋白质是由氨基酸组成的，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的一个新范式是，蛋白质在核糖体上合成或翻译的速度控制着蛋白质的最终命运，例如蛋白质是否正确地折叠、错误折叠、聚集或二聚，是否被移动到特定的细胞位置，或者以某种方式被加工以改变其功能。这个项目的目标是利用计算机模拟和理论来了解蛋白质合成速度对新生蛋白质行为的影响，包括蛋白质在翻译过程中的折叠和二聚化。通过该项目，将鼓励小学和高中妇女和少数民族学生接受STEM教育，使她们接触到计算生物物理学的尖端科学研究。这个项目还将使研究生接触到国际合作，这将帮助他们建立一个国际科学同事网络。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被证明可以影响密码子的转译率，以克服停滞序列。需要检验的假设是，在蛋白质合成过程中，新生链条所经历的拉力的大小受到许多因素的影响，包括折叠结构域的稳定性和大小。在第一个目标中，将通过在不同分辨率下使用分子模拟来验证这一假设，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，该假说假设快速翻译密码子可以通过加速容易错误折叠的片段的合成来最大化共翻译折叠，从而增加进入自然状态的通量。在最后一个目标中，研究人员将探索密码子转译率的变化可以改变蛋白质的功能，但不一定改变其溶解性的观察结果，这表明新生蛋白质的结构变化必须是适度的，否则可能会发生聚集。通过模拟异二聚化蛋白质的合成，并计算其结合亲和力如何随着密码子转译率的变化而变化，将研究这些结构重排的范围有多广。这项工作将对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。