Camacho C J, Weng Z, Vajda S, DeLisi C
Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215
Biophys J. 1999 Mar;76(3):1166-78. doi: 10.1016/S0006-3495(99)77281-4.
We report the computer generation of a high-density map of the thermodynamic properties of the diffusion-accessible encounter conformations of four receptor-ligand protein pairs, and use it to study the electrostatic and desolvation components of the free energy of association. Encounter complex conformations are generated by sampling the translational/rotational space of the ligand around the receptor, both at 5-A and zero surface-to-surface separations. We find that partial desolvation is always an important effect, and it becomes dominant for complexes in which one of the reactants is neutral or weakly charged. The interaction provides a slowly varying attractive force over a small but significant region of the molecular surface. In complexes with no strong charge complementarity this region surrounds the binding site, and the orientation of the ligand in the encounter conformation with the lowest desolvation free energy is similar to the one observed in the fully formed complex. Complexes with strong opposite charges exhibit two types of behavior. In the first group, represented by barnase/barstar, electrostatics exerts strong orientational steering toward the binding site, and desolvation provides some added adhesion within the local region of low electrostatic energy. In the second group, represented by the complex of kallikrein and pancreatic trypsin inhibitor, the overall stability results from the rather nonspecific electrostatic attraction, whereas the affinity toward the binding region is determined by desolvation interactions.
我们报告了通过计算机生成的四种受体 - 配体蛋白对扩散可及相遇构象的热力学性质高密度图谱，并利用该图谱研究结合自由能的静电和去溶剂化成分。通过在受体周围对配体的平移/旋转空间进行采样来生成相遇复合物构象，采样间距分别为5埃和零表面间距。我们发现部分去溶剂化始终是一个重要影响因素，对于其中一种反应物为中性或弱电荷的复合物，它变得占主导地位。这种相互作用在分子表面的一个小但重要的区域上提供了一个缓慢变化的吸引力。在没有强电荷互补性的复合物中，该区域围绕着结合位点，并且去溶剂化自由能最低的相遇构象中配体的取向与在完全形成的复合物中观察到的相似。具有强相反电荷的复合物表现出两种行为。在以巴纳酶/巴纳斯塔为例的第一组中，静电作用对结合位点施加强烈的取向引导，而去溶剂化在低静电能的局部区域内提供一些额外的粘附力。在以激肽释放酶和胰蛋白酶抑制剂复合物为例的第二组中，整体稳定性源于相当非特异性的静电吸引，而对结合区域的亲和力则由去溶剂化相互作用决定。
