THEORETICAL AND EXPERIMENTAL STUDIES OF COMPLEXATION

络合的理论和实验研究

• 批准号: 3303672
• 负责人: WILLIAM C STILL
• 金额: $ 16.5万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3303672
• 关键词: chemical association; chemical binding; chemical reaction; drug /agent; molecular dynamics; thermodynamics; water

The objective of this proposal is the development of methods by which free energies of association of medicinal agents and biological molecules in water can be calculated. Having such methods will provide significantly improved procedures by which new medicinal agents can be designed. Central to the calculation of association free energies is the calculation of solvation energies in water. We will develop a continuum model for water which will provide estimates of solvation free energies rapidly and analytically. This model will provide a potential of mean force for the aqueous environment and be implemented as a standard energy term in a molecular mechanics force field. We will use the solvation model in a molecular dynamics-based full free energy simulation to evaluate enthalpies and entropies (and thus free energies) of association. Our initial calculations will be carried out on the antibiotic ristocetin which binds intermediates in bacterial cell wall biosynthesis. Experimental work will include measurements of solvation free energies for both small and large molecules, synthesis of conformationally restricted host molecules, and measurement of binding constants in water as tests of the theoretical methods to be developed. In connection with our studies of conformationally restricted molecules, we will develop a sequential constraint Monte Carlo conformational searching method which will be applicable to polymacrocycles and large, flexible molecules having many nOe-constrained internuclear distances.

该提案的目的是开发自由的方法 药用剂与生物分子的缔合能量 可以计算水。拥有这样的方法将大量提供 可以设计新药剂的改进程序。中央 协会自由能的计算是计算 水中的溶能。我们将开发水的连续模型 这将迅速提供溶剂化自由能的估计，并且 分析。该模型将为该模型提供平均力的潜力 水性环境并作为标准能量术语实施 分子力学力场。我们将在 基于分子动力学的完整自由能模拟以评估焓 和关联的熵（以及自由的能量）。我们的最初 计算将在结合的抗生素ristocetin上进行 细菌细胞壁生物合成中的中间体。实验工作将 包括对大小的溶剂化自由能的测量 分子，构象限制的宿主分子的合成和 测量水中的结合常数作为理论的测试 要开发的方法。与我们的构象研究有关 限制分子，我们将开发一个顺序约束蒙特卡洛 构象搜索方法将适用于多头环 大，柔性分子，具有许多NOE受限的内膜 距离。