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ASSOCIATION OF ELONGATION FACTORS AND ANTIBIOTICS WITH THE RIBOSOME

延伸因子和抗生素与核糖体的关联

基本信息

批准号：
7537241
负责人：
JAMES ANDREW MCCAMMON
金额：
$ 3.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7537241
关键词：
Accounting Aminoglycoside Antibiotics Antibiotics Antibodies Bacteria Binding Binding Sites Biological Process Biology Biopolymers California Centrifugation Charge Complex Computers Cytoskeletal Proteins Diffuse Diffusion Disease EEF1A1 gene Electrostatics Elongation Factor Enzyme Kinetics Enzymes Event Gene Expression Genetic Genetic Code Genetic Transcription Genome Goals Grant Immune Immune response International Kinetics Knowledge Letters Ligands Macromolecular Complexes Measures Membrane Membrane Proteins Messenger RNA Metabolism Methods Modeling Modification Molecular Motion Mutation Names Nervous System Physiology Neurotransmitters Nucleic Acids Organism Peptide Elongation Factor G Peptides Play Poland Process Property Proteins Reaction Relative (related person)Research Ribonucleoproteins Ribosomes Role Signal Transduction Solvents Synapses System Techniques Thermodynamics Time Transfer RNA Translations Universities Work base design flexibility macromolecular assembly molecular dynamics mutant novel parent grant particle prevent receptor research study simulation tool

项目摘要

The main objective of this project is to determine the kinetics and energetics of binding of various ligands to the ribosome. These ligands include aminoglycoside antibiotics and their derivatives, elongation factors EF-Tu and EF-G and their proposed mutants. Timely and specific binding of these molecules is essential for the proper peptide formation in translation of the genetic code. EF-Tu and EF-G are crucial for, respectively, incorporating the aminoacylated tRNAs into the ribosome and for translocating both the tRNAs and mRNA after the peptide bond formation. Many antibiotics interfere with the binding of elongation factors, hinder the incorporation of the aminoacylated tRNA or inhibit functional conformational changes of the ribosome. The knowledge of what interactions govern the ligand encounter and binding with the ribosome will aid our understanding of the bi-molecular association, translation and inhibitory properties of antibiotics. The research will allow to propose experiments involving mutations of residues that prevent elongation factor binding and experiments suggesting derivatives of antibiotics that make their binding more specific. The effect of flexibility of ligands and the ribosome on association will be assessed. The techniques to study the energetics, thermodynamics, and kinetics of binding will include: molecular dynamics, Brownian dynamics and Poisson-Boltzmann implicit solvent models. Current simulation techniques will be extended and modified in order to enable the detailed studies of large macromolecular assemblies with over 200,000 atoms. The influence of long-range electrostatic steering will be investigated. The electrostatic similarity among the diffusing factors and complementarity with the ribosome binding site will be analyzed. The effect of flexibility of ligands and the ribosome on association will be assessed and the simulation methods will be extended to account for internal motions of the diffusing molecules. The project will promote international collaborative research between University of California at San Diego and Warsaw University in Poland. Blocking the ribosome function is important in curing many diseases, therefore, predictions of new molecules interfering with the ribosome are needed and this project will help to suggest them. The understanding of the mechanism governing the diffusion of molecules toward the ribosome could help in proposing novel antibiotics that bind stronger. This project will also help propose modifications of ribosome factors which hinder their correct association with the ribosome and prevent proper ribosome function.

本计画的主要目标是确定各种配体结合的动力学和能量学到核糖体。这些配体包括氨基糖苷类抗生素及其衍生物、延伸因子 EF-Tu和EF-G及其提出的突变体。这些分子的及时和特异性结合对于翻译中正确的肽形成至关重要遗传密码的一部分EF-Tu和EF-G分别对整合氨酰化的tRNA至关重要进入核糖体，并在肽键形成后转运tRNA和mRNA。许多抗生素干扰延伸因子的结合，阻碍氨基酰化的 tRNA或抑制核糖体的功能构象变化。了解什么样的相互作用控制配体的遭遇和与核糖体的结合将有助于我们理解双分子抗生素的缔合、翻译和抑制性质。该研究将允许提出涉及阻止延伸因子结合的残基突变的实验和实验这表明抗生素的衍生物使它们的结合更特异。配体柔性的影响并评估核糖体的结合。研究结合的能量学、热力学和动力学的技术将包括：动力学、布朗动力学和泊松-玻尔兹曼隐式溶剂模型。当前模拟技术将得到扩展和修改，以便能够详细研究大分子拥有超过20万个原子的集合体将研究远程静电转向的影响。扩散因子间的静电相似性及与核糖体结合位点的互补性将被分析。将评估配体和核糖体的柔性对缔合的影响，模拟方法将扩展到考虑扩散分子的内部运动。该项目将促进加州大学旧金山分校和美国加州大学旧金山分校之间的国际合作研究。迭戈和波兰华沙大学。阻断核糖体功能在治疗许多疾病中很重要，因此，干扰核糖体的分子是必需的，这个项目将有助于提出它们。的了解分子向核糖体扩散的机制有助于提出了结合力更强的新型抗生素。该项目还将有助于提出核糖体的修饰阻碍它们与核糖体正确结合并阻止核糖体正常功能的因子。