Collaborative Research: Unlocking the mechanism of tRNA translocation through the ribosome using large-scale molecular simulation

核糖体是驻留在活细胞内的分子工厂，负责读取源自DNA的遗传指令，并根据这些指令从氨基酸中组装蛋白质。核糖体通过锁定包含单个蛋白质分子的遗传指令的长串状分子信使RNA来读取遗传信息。核糖体必须将RNA的语言转换为蛋白质的语言。为了做到这一点，核糖体使用了另一类被称为转移RNA分子的RNA分子，它将RNA字母表转换为蛋白质字母表。在过去的40年里，核糖体的大部分研究都集中在转移RNA通过核糖体的运动上；然而，研究人员对确切的分子机制一无所知。直到最近，随着强大的超级计算机、单分子成像和相关的原子分辨率结构的出现，这个问题才能得到原子细节的解决。了解核糖体是如何工作的，可能会在生物启发的纳米计算机开发方面取得突破，帮助推动纳米技术产业。了解核糖体还可能带来对生命起源和遗传密码起源的新见解。本项目的目的是利用分子模拟和单分子成像相结合的方法研究核糖体头部旋转的机制。在头部旋转中，头部围绕颈部旋转，信使RNA链同时围绕颈部移动，转移RNA通过核糖体内部移动。将进行模拟，以了解在头部旋转过程中核糖体的全局运动。详细的模拟将对头部旋转的能量格局进行预测。荧光标记将被放置在核糖体上，通过单分子实验监测头部旋转随时间的变化。可以将这些相同的标签添加到模拟中，以获得模拟和实验之间的比较，并提供对实验的原子解释。该项目由生物科学局分子和细胞生物科学部的分子生物物理学和数学和物理科学局物理部的计算物理计划共同支持。

Ribosomes are molecular factories residing inside living cells responsible for reading genetic instructions originating in DNA and assembling proteins from amino acids based on these instructions. Ribosomes read genetic information by latching onto a long string-like molecule messenger RNA that contains the genetic instructions for one single protein molecule. The ribosome must convert the language of RNA into the language of protein. To accomplish this, the ribosome employs another class of RNA molecules called transfer RNA molecules, which convert the RNA alphabet into the protein alphabet. Much of ribosome research over the past 40 years has focused on the movement of transfer RNAs through the ribosome; however, the precise molecular mechanism has eluded researchers. It is only recently, with powerful supercomputers, single molecule imaging, and relevant atomic resolution structures, that this question can be addressed in atomic detail. Understanding how the ribosome works may lead to breakthroughs in the development of bio-inspired nanoscale computers, helping to fuel the nanotech industry. Understanding the ribosome may also lead to new insights into the origin of life and the origin of the genetic code. The objective of this project is to study mechanism of ribosome head swivel using an integrated approach of molecular simulations and single molecule imaging. In head swivel, the head pivots around the neck, while the messenger RNA strand moves simultaneously around the neck and the transfer RNA moves through the inside of the ribosome. Simulations will be performed to understand the global motions of the ribosome occurring during head swivel. Detailed simulations will produce predictions for the energy landscape of head swivel. Fluorescent labels will be placed on the ribosome to monitor head swivel as a function of time using single molecule experiments. These same labels can be added into simulations to obtain comparisons between simulation and experiment and provide atomistic interpretations of the experiments. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.