NMR AND MONTE CARLO STUDIES OF CATION-DNA INTERACTIONS

阳离子-DNA 相互作用的 NMR 和蒙特卡罗研究

• 批准号: 2177382
• 负责人: M. THOMAS RECORD
• 金额: $ 17.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2177382
• 关键词: DNA; barium; cations; cell differentiation; chemical binding; chemical chain length; conformation; electrolytes; hexamethonium compound; intermolecular interaction; ligands; mathematical model; model design /development; molecular dynamics; nitrogen; nuclear magnetic resonance spectroscopy; nucleic acid probes; polyamines; polymerization; polymers; radionuclides; radiotracer; sodium; stoichiometry; thermodynamics

The long-range objectives of this research are the development and application of accurate experimental and rigorous theoretical methods of investigating the molecular detail and thermodynamic consequences of the interactions of cations with nucleic acids. These studies are of fundamental importance in polyelectrolyte chemistry, and have direct applications to the analysis of the interactions of nucleic acids with charged ligands of biological interest, including proteins and therapeutic agents. The stability and specificity of nucleic acid conformations and of complexes with charged ligands in aqueous solution are often determined by the electrolytes present and by competitive ion exchange processes involving cations on DNA. Thermodynamic measurements characterizing processes (conformational changes, ligand-binding) involving polymeric or oligomeric nucleic acids will be analyzed and interpreted by using Grand Canonical Monte Carlo (GCMC) simulations and calculations based on the Poisson-Boltzmann (PB) cell model. In these analyses, the fundamental thermodynamic variables are preferential interaction coefficients which reflect all nonideality due to interactions of electrolyte(s) with the specified state of the oligo- or polyelectrolyte component. Our GCMC and PB methods will be developed further in order to analyze equilibrium dialysis data on four component systems (water, nucleic acid, salt, oligocationic ligand). Current thermodynamic descriptions of salt effects on the extent of association of charged ligands with DNA will be examined at a fundamental level using these preferential interaction coefficients. The interactions of small cations with oligomeric and polymeric DNA will be studied quantitatively by NMR measurements on suitable quadrupolar nuclei in cations of biophysical interest. The dependences of the longitudinal and transverse relaxation rates of the probe nuclei (such as 23Na, 14N and 135Ba) on degree of polymerization, solution composition, temperature and (where appropriate) field strength, will be determined and analyzed to quantify the extent of association of individual cations with DNA, and the relative affinities of pairs of competing cations. These results will be compared with theoretical predictions for corresponding model systems calculated by canonical Monte Carlo (CBC) simulations or the PB cell model. Information about the dynamic character of the association of small ions with oligo- and polymeric nucleic acids will be obtained from determinations of quadrupolar NMR correlation times.

这项研究的远程目标是发展和 精确实验和严格的理论方法的应用 研究分子细节和热力学后果 阳离子与核酸的相互作用。 这些研究是 在聚电解质化学中的基本重要性，并具有直接 应用核酸与核酸相互作用的应用 带电的生物学兴趣配体，包括蛋白质和治疗性 代理商。 核酸构象的稳定性和特异性和 水溶液中带有带电配体的配合物通常由 电解质存在以及通过竞争性离子交换过程 涉及DNA的阳离子。 热力学测量表征过程（构象 变化，配体结合）涉及聚合物或低聚核酸的变化 将通过使用大规范的蒙特卡洛对分析和解释 （GCMC）基于Poisson-Boltzmann（PB）的模拟和计算 细胞模型。 在这些分析中，基本的热力学变量是 优先相互作用系数，反映了由于 电解质与寡聚或寡素的指定状态的相互作用 聚电解质组件。 我们的GCMC和PB方法将开发 进一步分析四个成分的平衡透析数据 系统（水，核酸，盐，寡聚配体）。 当前的 盐的热力学描述对盐的影响 带有DNA的充电配体将在基本层面检查 这些优先的相互作用系数。 小阳离子与低聚和聚合物DNA的相互作用将是 通过NMR测量对合适的四极核进行定量研究 在生物物理兴趣的阳离子中。 纵向的依赖 探针核的横向松弛率（例如23NA，14N和 135BA）关于聚合度，溶液组成，温度和 （在适当的情况下）将确定并分析场强度 量化单个阳离子与DNA的关联程度， 对竞争阳离子对的相对亲和力。 这些结果将是 与相应模型系统的理论预测相比 通过规范的蒙特卡洛（CBC）模拟或PB细胞模型计算。 有关小离子关联的动态特征的信息 将从寡核酸和聚合物核酸中获得 确定四极NMR相关时间。