INCLUSION OF SOLVATION IN LIGAND BINDING FREE ENERGY CALCULATIONS

考虑到溶剂对分子强度的影响， 相互作用一直是分子生物学中的一个长期存在的问题， 一般计算和基于结构的药物设计， 特别的。 在这里，我们探讨了广义玻恩（GB/SA）模型， 溶剂化以计算配体-受体结合能。 GB/SA 这种方法允许估计静电，货车德瓦耳斯，和 疏水性对结合自由能的贡献。 GB/SA 公式化提供了计算速度和 这些计算的准确性。 我们推导出一个公式来估算 束缚自由能。 我们还制定了一个程序， 惩罚任何未被占用的嵌入空间， 配体和受体在对接过程中。 提高 计算速度，蛋白质对静电的贡献 筛选是预先计算并存储在网格上的。 细化 需要配体位置来优化非键合相互作用 在配体和受体之间。 我们的GB/SA算法版本需要 在Silicon Graphics R10000上每个方向大约10秒 工作站 在两个测试系统中，二氢叶酸还原酶和 胰蛋白酶，我们获得了更好的结果比目前的DOCK力 现场评分法 我们还提出了一种方法来确定一个 适当的参数制度，以平衡特异性和 方程的一般性。

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.