Large-scale simulations of ribosomal decoding

 描述(申请人提供)：更高分辨率低温电子显微镜和真核核糖体结构的出现为核糖体机制领域开辟了广阔的可能性。最近，我们与克里斯蒂安·斯潘的冷冻-EM实验室一起，发表了与解码相关的各种功能状态下的人类核糖体的首批全原子模型之一。使用我们的MDfit方法，我们生产出了与低温电磁密度高度一致的模型。这项研究揭示了真核生物特有的一种新的构象变化：亚基滚动。我们还对tRNA适应细菌核糖体进行了广泛的研究。在这里，我们将研究亚单位滚动对哺乳动物核糖体解码过程中调节的影响。我们还将研究在解码之前和适应之后发生的构象变化。通过对人类和细菌核糖体机制的比较，我们希望对抗生素的作用机制有更深入的了解。我们将结合使用显式溶剂和全原子简化描述技术，以我们以前的出版物为基础。我们还将扩展我们的MDfit技术，以获得更高分辨率的低温电磁密度。

 DESCRIPTION (provided by applicant): The advent of higher resolution cryo electron microscopy and structures of eukaryotic ribosomes has opened the field of ribosome mechanism to a vast array of possibilities. Together with the Christian Spahn cryo-EM lab, we recently published one of the first all-atom models of the human ribosome in various functional states related to decoding. Using our MDfit method, we produced models highly consistent with cryo-EM density. The study revealed a new conformational change specific to eukaryotes: subunit rolling. We have also performed extensive studies on tRNA accommodation into the bacterial ribosome. Here, we will investigate the effect of subunit rolling on accommodation during decoding by the mammalian ribosome. We will also study conformational changes occurring prior to decoding and after accommodation. By comparing human and bacterial ribosome mechanism, we hope to gain insight into antibiotic action mechanism. We will use a combination of explicit solvent and all-atom reduced description techniques based on our previous publications. We will also extend our MDfit technique for higher resolution cryo-EM density.