THEORETICAL AND EXPERIMENTAL STUDIES OF COMPLEXATION

络合的理论和实验研究

• 批准号: 3303671
• 负责人: WILLIAM C STILL
• 金额: $ 15.89万
• 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/3303671
• 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.

本提案的目标是开发免费的方法