Large-scale simulations of ribosomal decoding

多重耐药细菌在美国医院中呈现出日益严重的问题。设计新的抗生素 对这些细菌有效，了解药物与靶标的相互作用和靶标非常重要 他们自己。我们将研究一个主要的抗生素靶标：核糖体。许多核糖体抗生素会干扰 核糖体解码的过程（“tRNA 选择”）。解码的限速步骤为 调节，tRNA 从部分结合状态（A/T 状态）移动到完全结合位置 （A/A 状态）在核糖体内。结构生物学技术已经确定了结构 核糖体住宿前后。动力学实验已经确定了调节率。它 然而，通过实验研究原子细节的调节过程是很困难的 抗生素的详细作用。虽然分子动力学模拟已被用来表征 较小的蛋白质复合物中的自发转变，核糖体的大尺寸和复杂性 对核糖体进行了类似的研究，但计算量却令人望而却步。在我们的初步数据中，我们有 将洛斯阿拉莫斯国家实验室的高性能计算资源与全原子结合起来 研究 tRNA 进入核糖体的简化模型潜力。在这里，我们将使用大 规模分子模拟来研究调节的关键特征和抗生素的影响。我们会 将分子动力学与单分子研究紧密结合起来，形成更连贯的图景 核糖体解码。

Multi-drug resistant bacteria present an increasing problem in US hospitals. To design new antibiotics that are effective against these bacteria, it is important to understand drug-target interactions and the targets themselves. We will study a major antibiotic target: the ribosome. Many ribosome antibiotics interfere with the process of decoding by the ribosome ("tRNA selection"). The rate-limiting step of decoding is accommodation, where the tRNA moves from a partially bound state (A/T state) to its fully bound position (A/A state) inside the ribosome. Structural biology techniques have determined the structure of the ribosome before and after accommodation. Kinetic experiments have determined accommodation rates. It is difficult, however, to study the process of accommodation in atomic detail experimentally and the detailed effects of antibiotics. While molecular dynamics simulations have been used to characterize spontaneous transitions in smaller protein complexes, the large size and complexity of the ribosome have made similar studies of the ribosome computationally prohibitive. In our preliminary data, we have combined the high performance computing resources at Los Alamos National Laboratory with all-atom reduced-model potentials to study accommodation of tRNA into the ribosome. Here, we will use large- scale molecular simulation to study key features of accommodation and the effects of antibiotics. We will closely integrate molecular dynamics with single molecule studies to form a more coherent picture of ribosome decoding.