Large-scale simulations of ribosomal decoding

多重耐药细菌在美国医院中造成了越来越多的问题。设计新的抗生素， 对这些细菌有效，重要的是要了解药物-靶标相互作用和靶标 自己我们将研究一个主要的抗生素靶点：核糖体。许多核糖体抗生素干扰 核糖体的解码过程（“tRNA选择”）。解码的速率限制步骤是 调节，其中tRNA从部分结合状态（A/T状态）移动到其完全结合位置 （A/A状态）核糖体内。结构生物学技术已经确定了 核糖体在调节之前和之后。动力学实验已经确定了调节率。它 然而，很难在实验上研究原子细节的调节过程， 抗生素的详细效果。虽然分子动力学模拟已经被用来表征 在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， 使得对核糖体的类似研究在计算上受到限制。在我们的初步数据中， 将洛斯阿拉莫斯国家实验室的高性能计算资源与全原子相结合， 简化模型的潜力，研究住宿的tRNA进入核糖体。在这里，我们将使用大- 大规模分子模拟研究适应的关键特征和抗生素的影响。我们将 将分子动力学与单分子研究紧密结合，以形成更连贯的图像， 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.