Nauchitel V, Villaverde M C, Sussman F
Oklahoma University Health Sciences Center, Oklahoma City 73104, USA.
Protein Sci. 1995 Jul;4(7):1356-64. doi: 10.1002/pro.5560040711.
We have developed a simple approach for the evaluation of the free energies of inhibitor binding to the protease of the human immunodeficiency virus (HIV-1 PR). Our algorithm is based on the observation that most groups that line the binding pockets of this enzyme are hydrophobic in nature. Based on this fact, we have likened the binding of an inhibitor to this enzyme to its transfer from water to a medium of lower polarity. The resulting expression produced values for the free energy of binding of inhibitors to the HIV-1 PR that are in good agreement with experimental values. The additive nature of this approach has enabled us to partition the free energy of binding into the contributions of single fragments. The resulting analysis clearly indicates the existence of a ranking in the participation of the enzyme's subsites in binding. Although all the enzyme's pockets contribute to binding, the ones that bind the P2-P'2 span of the inhibitor are in general the most critical for high inhibitor potency. Moreover, our method has allowed us to determine the nature of the functional groups that fit into given enzyme binding pockets. Perusal of the energy contributions of single side chains has shown that a large number of hydrophobic and aromatic groups located in the central portion of the HIV-1 PR inhibitors present optimal binding. All of these observations are in agreement with experimental evidence, providing a validation for the physical relevancy of our model.
我们已经开发出一种简单的方法来评估抑制剂与人类免疫缺陷病毒蛋白酶（HIV-1 PR）结合的自由能。我们的算法基于这样的观察：构成该酶结合口袋内壁的大多数基团本质上是疏水的。基于这一事实，我们将抑制剂与该酶的结合比作其从水转移到低极性介质中。由此产生的表达式得出的抑制剂与HIV-1 PR结合的自由能值与实验值高度吻合。这种方法的加和性使我们能够将结合自由能划分为单个片段的贡献。由此产生的分析清楚地表明，该酶亚位点在结合中的参与存在一个排序。虽然该酶的所有口袋都对结合有贡献，但结合抑制剂P2-P'2跨度的口袋通常对高抑制剂效力最为关键。此外，我们的方法使我们能够确定适合特定酶结合口袋的官能团的性质。对单个侧链能量贡献的研读表明，位于HIV-1 PR抑制剂中心部分的大量疏水和芳香基团呈现出最佳结合。所有这些观察结果都与实验证据一致，为我们模型的物理相关性提供了验证。
