THEORETICAL AND EXPERIMENTAL STUDIES OF COMPLEXATION

这项建议的目的是制定方法， 药物和生物分子的结合能 水是可以计算的。拥有这些方法将大大提供 改进的程序，通过这些程序可以设计新的药剂。中央 结合自由能的计算是 水的溶剂化能量我们将建立一个水的连续模型 这将快速提供溶剂化自由能的估计， 分析。该模型将提供一个潜在的平均力， 水环境，并作为一个标准的能源条款， 分子力学力场我们将使用溶剂化模型在一个 基于分子动力学的全自由能模拟来评估分子量 和熵（以及自由能）。我们最初 将对抗生素利托那韦进行计算， 细菌细胞壁生物合成的中间体。实验工作将 包括对小分子和大分子溶剂化自由能测量 分子，合成构象受限的主体分子，以及 测定水中的结合常数作为理论 方法有待开发。结合我们对构象的研究， 限制分子，我们将开发一个顺序约束蒙特卡罗 一种适用于多环大环化合物的构象搜索方法 以及具有许多nOe约束的核间 的距离.

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.