INCLUSION OF SOLVATION IN LIGAND BINDING FREE ENERGY CALCULATIONS

考虑溶剂对分子强度的影响 相互作用是一个长期存在的分子问题。 一般计算和基于结构的药物设计 很特别。在这里，我们探索了广义出生(GB/SA)模型 计算配体-受体结合能的溶剂化作用。GB/SA 该方法允许估计静电、范德瓦尔斯和 疏水对结合自由能的贡献。GB/SA 公式提供了计算速度和计算速度之间的良好平衡 这些计算的准确性。我们已经推导出一个估算公式。 结合自由能。我们还开发了一种程序来 惩罚可能形成于 配体和受体在对接过程中。为了改善 计算速度，蛋白质对静电的贡献 筛选是预先计算的，并存储在网格中。改进了 配基位置是优化非键相互作用所必需的 在配体和受体之间。我们版本的GB/SA算法需要 Silicon Graphics R10000上的每个方向大约10秒 工作站。在两个测试系统中，二氢叶酸还原酶和 胰酶，我们得到了比现在的对接力好得多的结果 现场计分方法。我们还建议使用一种方法来识别 适当的参数制度，以平衡特定性和 方程式的一般性。

Accounting for the effect of solvent on the strength of molecular interactions has been a long-standing problem for molecular calculations in general and for structure-based drug design in particular. Here, we explore the generalized-Born (GB/SA) model of solvation to calculate ligand-receptor binding energies. The GB/SA approach allows the estimation of electrostatic, van der Waals, and hydrophobic contributions to the free energy of binding. The GB/SA formulation provides a good balance between computational speed and accuracy in these calculations. We have derived a formula to estimate the binding free energy. We have also developed a procedure to penalize any unoccupied embedded space that might form between the ligand and the receptor during docking processes. To improve the computational speed, the protein contribution to the electrostatic screening is pre-calculated and stored on a grid. Refinement of the ligand position is required to optimize the non-bonded interactions between ligand and receptor. Our version of the GB/SA algorithm takes approximately 10 seconds per orientation on a Silicon Graphics R10000 workstation. In two test systems, dihydrofolate reductase and trypsin, we obtain much better results than the current DOCK force field scoring method. We also suggest a methodology to identify an appropriate parameter regime to balance the specificity and the generality of the equations.