ASSOCIATION OF ELONGATION FACTORS AND ANTIBIOTICS WITH THE RIBOSOME

这个项目的主要目标是确定各种配体结合的动力学和能量学。 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及其建议的突变体。 这些分子的及时和特定的结合对于翻译中正确的多肽形成是必不可少的。 遗传密码。EF-Tu和EF-G分别对整合氨基酰化tRNA至关重要 进入核糖体，并在肽键形成后转移tRNAs和mRNAs。许多 抗生素干扰延伸因子的结合，阻碍氨基酰化的掺入 TRNA或抑制核糖体的功能性构象变化。了解哪些相互作用 控制配体的相遇和与核糖体的结合将有助于我们对双分子的理解 抗生素的缔合、翻译和抑制特性。这项研究将允许提出 涉及阻止延伸因子结合的残基突变的实验和实验 建议使用抗生素的衍生物，使它们的结合更具特异性。配体的柔性效应 并对结合的核糖体进行评估。 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。电流模拟 技术将得到扩展和改进，以便能够对大分子进行详细研究 超过200,000个原子的组件。研究了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部位的互补性 将会被分析。将评估配体和核糖体的灵活性对结合的影响，并 模拟方法将被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之间的国际合作研究 迭戈和波兰的华沙大学。 阻断核糖体功能在治疗许多疾病中是重要的，因此，新的预测 需要干扰核糖体的分子，这个项目将有助于提出它们。这个 了解分子向核糖体扩散的机制有助于 提出更具约束力的新型抗生素。该项目还将有助于提出对核糖体的修饰。 阻碍它们与核糖体正确结合并阻碍核糖体正常功能的因素。

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.