THERETICAL STUDIES OF DRUG-NUCLEIC ACID INTERACTIONS

该项目的长期目标是改进基于计算机的仿真 方法，可应用于研究结构，动力学和 核酸热力学及其与配体的相互作用。 在 在下一个赠款支持期，我们预计将在以下方面取得重大进展： 用于描述核酸的能量函数，以及方法中 确定构象自由能，突变的自由能， 核酸和核酸结合的绝对自由能 酸-配体络合物，使用分子动力学/自由能方法。 我们 计划使用可用的X射线和NMR数据来评估我们的模型。 应用于许多最有趣的物理化学 DNA和RNA的结构和热力学现象将进行 包括AT碱基对的疏Z性，RNA的热力学， 环，序列选择性和结合DNA小沟结合 配体，以及配体与DNA结合的邻居排除规则。 最新的进展是允许一个最令人兴奋的协同作用， 研究分子间相互作用的理论方法和实验。 这些计算机模拟产生了比以往任何时候都更准确的见解 在此之前，并经常正确地预测随后的结果 实验这里提出的工作具有协同关系， 实验，旨在持续提高预测能力 这些基于计算机的理论方法。我们的长远目标 研究的目的是使基于计算机的方法真正可靠， 预测并将其用于抗癌和抗艾滋病药物设计。

The long term goal of this project is to improve computer based simulation methods that can be applied to study the structures, kinetics and thermodynamics of nucleic acids and their interaction with ligands. In the next period of grant support, we anticipate making major improvements in the energy function used to describe nucleic acids, and in the methodology to determine conformational free energies, free energies for mutations, and absolute free energies of association for nucleic acids and nucleic acid-ligand complexes using molecular dynamics/free energy approaches. We plan to use available X-ray and NMR data to evaluate our models. Applications to a number of the most interesting physical chemical phenomena in DNA and RNA structure and thermodynamics will be carried out including the Z phobicity of AT base pairs, the thermodynamics of RNA loops, the sequence selectivity and binding of DNA minor groove binding ligands, and the neighbor exclusion rule for ligand binding to DNA. Recent advances are allowing a most exciting synergy between computer based theoretical methods to study intermolecular inter-actions and experiments. These computer simulations are yielding more accurate insights than ever before and are often correctly predicting the results of subsequent experiments. The work proposed here has such a synergistic relationship to experiments and is aimed at a continued improvement of the predictive power of these computer based theoretical methods. The long term objective of our studies is to make the computer based approaches truly reliable and predictive and to use them in anti-cancer and anti-AIDS drug design.