Radmer R J, Kollman P A
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
J Comput Aided Mol Des. 1998 May;12(3):215-27. doi: 10.1023/a:1007905722422.
Three approximate free energy calculation methods are examined and applied to an example ligand design problem. The first of the methods uses a single simulation to estimate the relative binding free energies for related ligands that are not simulated. The second method is similar, except that it uses only first derivatives of free energy with respect to atomic parameters (most often charge, van der Waals equilibrium distance, and van der Waals well depth) to calculate free energy differences. The last method PROFEC (Pictorial Representation of Free Energy Components), generates contour maps that show how binding free energy changes when additional particles are added near the ligand. These three methods are applied to a benzamidine/trypsin complex. They each reproduce the general trends in the binding free energies, indicating that they might be useful for suggesting how ligands could be modified to improve binding and, consequently, useful in structure-based drug design.
研究了三种近似自由能计算方法，并将其应用于一个示例配体设计问题。第一种方法使用单个模拟来估计未模拟的相关配体的相对结合自由能。第二种方法类似，只是它仅使用自由能相对于原子参数（最常见的是电荷、范德华平衡距离和范德华阱深度）的一阶导数来计算自由能差。最后一种方法PROFEC（自由能成分的图形表示）生成等高线图，显示当在配体附近添加额外粒子时结合自由能如何变化。这三种方法应用于苯甲脒/胰蛋白酶复合物。它们各自再现了结合自由能的一般趋势，表明它们可能有助于提示如何修饰配体以改善结合，因此在基于结构的药物设计中有用。
