HEAT-CAPACITY CHANGES AND HYDROPHOBIC INTERACTIONS IN THE BINDING OF FK506 AND RAPAMYCIN TO THE FK506 BINDING-PROTEIN
HEAT-CAPACITY CHANGES AND HYDROPHOBIC INTERACTIONS IN THE BINDING OF FK506 AND RAPAMYCIN TO THE FK506 BINDING-PROTEIN
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DOI：
10.1073/pnas.89.11.4781
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发表时间：
1992-06-01
影响因子：
11.1
通讯作者：
THOMSON, JA
中科院分区：
文献类型：
--
作者：
CONNELLY, PR;THOMSON, JA
蛋白质/配体界面上的非极性部分之间以及这些非极性基团与水之间的不同相互作用，统称为疏水相互作用，被广泛认为对蛋白质/配体复合体的稳定性做出了重要的能量贡献。为了药物设计的目的，对疏水相互作用的定量估计及其结构基础的评估对于获得基于结构的结合自由能的预测是必不可少的。两种主要非极性的免疫抑制剂，FK506和雷帕霉素，都与一种称为FK506结合蛋白(FKBP-12)的小肽基脯氨酸顺反异构酶(FKBP-12)上的共同疏水口袋具有高亲和力，并抑制其活性。为了阐明这些配体的结构特征，我们对FK506和雷帕霉素与FKBP-12结合的热力学进行了研究。结合能在一定温度范围内用高精度的滴定量热法测定，从而可以估计热容的变化。通过结晶学数据分析FK506与FKBP-12结合时溶剂可及表面积的变化分布，发现99%的结合时埋入的净表面涉及非极性基团。这导致了FK506结合的热容变化，归一化到非极性表面的量，-0.40+/-0.02cal.K-1.mol-1 angstrom-2(1Cal=4.18J)，与疏水物质的水溶解得到的值相似。考虑到疏水相互作用过程的一般性质，我们对观察结果进行了讨论。
Differential interactions among nonpolar moieties at protein/ligand interfaces, and of these nonpolar groups with water, collectively termed hydrophobic interactions, are widely believed to make important energetic contributions to the stability of protein/ligand complexes. Quantitative estimates of hydrophobic interactions, and an evaluation of their structural basis, are essential for obtaining structure-based predictions of the free energies of binding for the purpose of drug design. Two largely nonpolar, immunosuppressive agents, FK506 and rapamycin, each bind with high affinity to a common hydrophobic pocket on a small peptidylproline cis-trans isomerase known as FK506 binding protein (FKBP-12) and inhibit its activity. In an effort to elucidate the structural features of these ligands responsible for the observed energetics, we have undertaken an investigation of the thermodynamics of binding of FK506 and rapamycin to FKBP-12. Enthalpies of binding have been determined by high-precision titration calorimetry over a range of temperature, allowing estimates of heat capacity changes. By analyzing the distribution of changes in solvent-accessible surface area upon binding of FK506 to FKBP-12 from crystallographic data, it is found that 99% of the net surface buried upon binding involves nonpolar groups. This leads to a heat capacity change of FK506 binding, normalized to the amount of nonpolar surface, of -0.40 +/- 0.02 cal.K-1.mol-1.angstrom-2 (1 Cal = 4.18 J), a value similar to that obtained for the aqueous dissolution of hydrophobic substances. Our observations are discussed in view of the general nature of hydrophobic interaction processes.