Large-Scale Simulations of Ribosomal Decoding

多重耐药细菌在美国医院出现了越来越多的问题。设计新的抗生素 对这些细菌是有效的，重要的是了解药物与靶点的相互作用和 目标本身。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 干扰核糖体的解码过程(“tRNA选择”)。的限速步骤 解码就是适应， 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) 在核糖体内部。结构生物学技术已经确定了核糖体的结构 住宿前和住宿后。动力学实验已经确定了住宿率。它是 然而，很难在实验上研究原子细节的调节过程。分子 动力学模拟已经被用来研究蛋白质折叠。然而，直到最近， 核糖体已经使核糖体构象变化的模拟在计算上变得难以实现。我们 将使用大规模分子模拟来研究调节的关键特征，包括 延长因子EF-Tu及抗生素的影响。我们还将结合分子动力学 扩散计算和测量的动力学 费率，以估算与这些测量的费率对应的住宿障碍高度。

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. Kinetics experiments have determined accommodation rates. It is difficult, however, to study the process of accommodation in atomic detail experimentally. Molecular dynamics simulations have been used to study protein folding. However, until recently, the size of the ribosome has made simulations of ribosome conformational changes computationally prohibitive. We will use large-scale molecular simulation to study key features of accommodation, including the effect of the elongation factor EF-Tu and the effect of antibiotics. We will also combine molecular dynamics diffusion calculations together with measured kinetic rates to estimate accommodation barrier heights that correspond to these measured rates.