Large-scale simulations of ribosomal decoding

核糖体解码的大规模模拟

基本信息

批准号：
10157895
负责人：
Karissa Y Sanbonmatsu
金额：
$ 34.03万
依托单位：
TRIAD NATIONAL SECURITY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157895
关键词：
Address Affect Anisotropy Antibiotic Resistance Antibiotics Bacteria Bacterial Infections COVID-19 pandemic Cessation of life Complex Cryoelectron Microscopy Data Discrimination Doxycycline Drug Targeting Dyes Electrostatics Equation Equilibrium Event Fluorescence Resonance Energy Transfer Future Head High Performance Computing Hospitals Kinetics Label Laboratories Length Ligands Measurement Methods Modeling Molecular Molecular Conformation Movement Multiple Bacterial Drug Resistance Noise Pharmaceutical Preparations Photons Positioning Attribute Process Proteins Resistance Resolution Ribosomes Sampling Signal Transduction Structure System Techniques Testing Time Transfer RNA aerobic respiration control protein base computing resources design drug resistant bacteria experimental study improved information processing kinetic theory large scale simulation mechanical properties molecular dynamics molecular modeling molecular scale mutant protein complex resistance mutation simulation single molecule single-molecule FRET statistics structural biology supercomputer triplet state

项目摘要

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.

多药物抗性细菌在美国医院中提出了越来越多的问题。设计新的抗生素对这些细菌有效，了解药物目标相互作用和目标很重要自己。我们将研究一个主要的抗生素靶标：核糖体。许多核糖体抗生素干扰核糖体解码的过程（“ tRNA选择”）。解码的限速步骤是住宿，tRNA从部分结合的状态（a/t状态）移动到其完全绑定的位置（A/A状态）核糖体内部。结构生物学技术已经确定了核糖体前后。动力学实验已确定可容纳率。它但是，很难在实验中研究原子细节的适应过程抗生素的详细作用。而分子动力学模拟已被用来表征在较小的蛋白质复合物中自发过渡，核糖体的较大尺寸和复杂性具有对核糖体计算过敏的类似研究。在我们的初步数据中，我们有将Los Alamos国家实验室的高性能计算资源与All-Atom结合在一起降低了模型的潜在，以研究tRNA进入核糖体。在这里，我们将使用大型比例分子模拟，以研究适应性的关键特征和抗生素的作用。我们将紧密整合分子动力学与单分子研究，形成更连贯的图片核糖体解码。