ASSOCIATION OF ELONGATION FACTORS AND ANTIBIOTICS WITH THE RIBOSOME

延伸因子和抗生素与核糖体的关联

• 批准号: 7173057
• 负责人: JAMES ANDREW MCCAMMON
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/7173057
• 关键词: Accounting; Aminoglycoside Antibiotics; Antibiotics; Antibodies; Bacteria; Binding; Binding Sites; Biological Process; Biology; Biopolymers; California; Centrifugation; Charge; Chromosome Pairing; 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; Numbers; Object Attachment; Organism; Peptide Elongation Factor G; Peptide Elongation Factor Tu; Peptides; Play; Pliability; Poland; Process; Property; Proteins; Range; Rate; Reaction; Relative (related person); Research; Ribonucleoproteins; Ribosomes; Role; Signal Transduction; Solvents; Synapses; System; Techniques; Thermodynamics; Time; Transfer RNA; Translations; Universities; Work; base; design; human EEF1A1 protein; macromolecular assembly; molecular dynamics; mutant; novel; parent grant; particle; prevent; receptor; research study; simulation; size; tool

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本项目的主要目的是确定各种配体与核糖体结合的动力学和能量学。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及其拟议的突变体。这些分子的及时和特异性结合对于遗传密码翻译中的适当肽形成至关重要。EF-Tu和EF-G分别对于将氨酰化的tRNA整合到核糖体中以及在肽键形成后转运tRNA和mRNA至关重要。许多抗生素干扰延伸因子的结合，阻碍氨酰化tRNA的掺入或抑制核糖体的功能构象变化。什么样的相互作用支配配体的遭遇和与核糖体的结合的知识将有助于我们理解抗生素的双分子缔合，翻译和抑制特性。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，以及建议抗生素衍生物使其结合更特异性的实验。将评估配体和核糖体的柔性对缔合的影响。研究结合的能量学、热力学和动力学的技术包括：分子动力学、布朗动力学和泊松-玻尔兹曼隐式溶剂模型。目前的模拟技术将得到扩展和修改，以便能够详细研究超过20万个原子的大分子组装体。将研究远程静电转向的影响。将分析扩散因子之间的静电相似性和与核糖体结合位点的互补性。的配体和核糖体的灵活性对协会的影响将进行评估和模拟方法将扩展到考虑扩散分子的内部运动。该项目将促进圣地亚哥的加州大学和波兰的华沙大学之间的国际合作研究。阻断核糖体功能在治疗许多疾病中很重要，因此，需要预测干扰核糖体的新分子，该项目将有助于提出它们。对控制分子向核糖体扩散的机制的理解有助于提出结合更强的新型抗生素。该项目还将有助于提出核糖体因子的修饰，这些修饰阻碍了它们与核糖体的正确结合并阻止了核糖体的正常功能。