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

核糖体是存在于活细胞内的分子工厂，负责阅读源自DNA的遗传指令并基于这些指令从氨基酸组装蛋白质。核糖体通过锁定一个长的类似分子的信使RNA来读取遗传信息，信使RNA包含一个单一蛋白质分子的遗传指令。核糖体必须将RNA的语言转换成蛋白质的语言。为了实现这一点，核糖体使用另一类RNA分子，称为转移RNA分子，将RNA字母转化为蛋白质字母。在过去的40年里，大部分核糖体研究都集中在转移RNA通过核糖体的运动上;然而，研究人员却没有找到精确的分子机制。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，这个问题才能在原子细节上得到解决。了解核糖体如何工作可能会导致生物启发的纳米计算机的发展取得突破，有助于推动纳米技术产业。了解核糖体也可能导致对生命起源和遗传密码起源的新见解。本研究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，而信使RNA链同时围绕颈部移动，转移RNA穿过核糖体内部移动。将进行模拟以了解头部旋转期间发生的核糖体的全局运动。详细的模拟将产生对头部旋转的能量景观的预测。荧光标记将被放置在核糖体上，以使用单分子实验监测头部旋转作为时间的函数。这些相同的标签可以添加到模拟中，以获得模拟和实验之间的比较，并提供实验的原子解释。该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学以及数学和物理科学理事会物理学部的计算物理学项目共同支持。

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.