Rejto P A, Verkhivker G M
Agouron Pharmaceuticals Inc., San Diego, California 92121, USA.
Proteins. 1997 Jul;28(3):313-24.
Mean field analysis of FKBP12 complexes with FK506 and rapamycin has been performed by using structures obtained from molecular docking simulations on a simple, yet robust molecular recognition energy landscape. When crystallographic water molecules are included in the simulations as an extension of the FKBP12 protein surface, there is an appreciable stability gap between the energy of the native FKBP12-FK506 complex and energies of conformations with the "native-like" binding mode. By contrast, the energy spectrum of the FKBP12-rapamycin complex is dense regardless of the presence of the water molecules. The stability gap in the FKBP12-FK506 system is determined by two critical water molecules from the effector region that participate in a network of specific hydrogen bond interactions. This interaction pattern protects the integrity and precision of the composite ligand-protein effector surface in the binary FKBP12-FK506 complex and is preserved in the crystal structure of the FKBP12-FK506-calcineurin ternary complex. These features of the binding energy landscapes provide useful insights into specific and nonspecific aspects of FK506 and rapamycin recognition.
通过在一个简单却稳健的分子识别能量景观上利用分子对接模拟获得的结构，对FKBP12与FK506和雷帕霉素的复合物进行了平均场分析。当在模拟中将结晶水分子作为FKBP12蛋白质表面的延伸包含在内时，天然FKBP12 - FK506复合物的能量与具有“类天然”结合模式的构象能量之间存在明显的稳定性差距。相比之下，无论水分子是否存在，FKBP12 - 雷帕霉素复合物的能谱都是密集的。FKBP12 - FK506系统中的稳定性差距由效应器区域的两个关键水分子决定，这两个水分子参与特定氢键相互作用网络。这种相互作用模式保护了二元FKBP12 - FK506复合物中复合配体 - 蛋白质效应器表面的完整性和精确性，并在FKBP12 - FK506 - 钙调神经磷酸酶三元复合物的晶体结构中得以保留。结合能量景观的这些特征为FK506和雷帕霉素识别的特异性和非特异性方面提供了有用的见解。
