Computational Methods for Determining Binding Free Energies

该提案的主要组成部分是开发旨在大幅增加生物分子系统范围的方法，先进的计算对接和设计方法可以应用于这些系统。迄今为止，最成功的方法和应用仅限于晶体结构已知的蛋白质，以及在复杂形成过程中保持相对刚性的蛋白质。限制对侧链和主干改变构象的更一般系统进行分析的主要障碍是目标函数。因此，该建议侧重于获得准确，可快速评估的半经验自由能函数的方法，特别强调溶剂化。其中包括消除当前半经验自由能函数所需的时间密集表面积计算的方法，以及几种新的溶剂化方法。可以充分利用自由能-目标函数的对接算法也将在各种应用中开发和测试，利用广泛的晶体学和热力学数据库。将注意系统地比较目前可用的和新出现的半经验自由能评价程序，包括划定它们的适用范围。J

The major component of the proposal is the development of methods designed to substantially increase the range of biomolecular systems to which advanced computational docking and design methodologies can be applied. The most successful methods and applications to date have been limited to proteins whose crystal structures are known, and which remain relatively rigid during complex formation. The main obstacle limiting the analysis of more general systems in which side chains and backbones change conformation is the target function. The proposal therefore focuses on methods for obtaining accurate, rapidly evaluatable semi-empirical free energy functions, with particular emphasis on solvation. These include methods for eliminating the time intensive surface area calculations required by current semi-empirical free energy functions, as well as several new approaches to solvation. Docking algorithms that can take full advantage of free energy- target functions will also be developed and tested in a variety of applications, exploiting the extensive crystallographic and thermodynamic databases available. Attention will be given to the systematic comparison of currently available and emerging semi-empirical free energy evaluation procedures, including the delineation of their range of applicability. J