THEORETICAL AND EXPERIMENTAL STUDIES OF COMPLEXATION

这项提议的目标是开发免费的方法 药物与生物分子的缔合能 水是可以计算的。拥有这样的方法将极大地提供 改进了设计新药剂的程序。中环 关于缔合自由能的计算是 水中的溶剂化能。我们将开发一个水的连续介质模型 它将快速提供溶剂化自由能的估计值 从分析上看。这个模型将提供平均作用力的势 水环境，并作为标准能量项在 分子力学力场。我们将使用溶剂化模型在 基于分子动力学的全自由能模拟计算热焓 以及缔合的熵(从而自由能)。我们最初的 将对结合在一起的抗生素瑞斯托星进行计算 细菌细胞壁生物合成的中间体。试验性工作将 包括小的和大的溶剂化自由能的测量 分子，构象受限的宿主分子的合成，以及 作为理论检验的水中结合常数的测量 方法有待开发。与我们的构象研究有关 受限分子，我们将发展一种序列约束蒙特卡罗方法 适用于多大环的构象搜索方法 和具有许多NOE约束的核间的大的、柔性的分子 距离。

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.