Li Zheng, Lazaridis Themis
Department of Chemistry, City College of New York/CUNY, Convent Ave & 138th Street, New York, New York 10031, USA.
J Phys Chem B. 2006 Jan 26;110(3):1464-75. doi: 10.1021/jp056020a.
The structure of the complex of cyclophilin A (CypA) with cyclosporin A (CsA, 1) shows a cluster of four water molecules buried at the binding interface, which is rearranged when CsA is replaced by (5-hydroxynorvaline)-2-cyclosporin (2). The thermodynamic contributions of each bound water molecule in the two complexes are explored with the inhomogeneous fluid solvation theory and molecular dynamics simulations. Water (WTR) 133 in complex 1 contributes little to the binding affinity, while WTR6 and 7 in complex 2 play an essential role in mediating protein-ligand binding with a hydrogen bond network. The calculations reveal that the rearrangement of the water molecules contributes favorably to the binding affinity, even though one of them is displaced going from ligand 1 to 2. Another favorable contribution comes from the larger protein-ligand interactions of ligand 2. However, these favorable contributions are not sufficient to overcome the unfavorable desolvation free energy change and the conformational entropy of the hydroxylpropyl group of ligand 2 in the complex, leading to a lower binding affinity of ligand 2. These physical insights may be useful in the development of improved scoring functions for binding affinity prediction.
亲环蛋白A（CypA）与环孢菌素A（CsA，1）形成的复合物结构显示，在结合界面处有四个水分子形成的簇，当CsA被（5-羟基正缬氨酸）-2-环孢菌素（2）取代时，该簇会重新排列。利用非均匀流体溶剂化理论和分子动力学模拟探究了两种复合物中每个结合水分子的热力学贡献。复合物1中的水分子（WTR）133对结合亲和力贡献很小，而复合物2中的WTR6和WTR7通过氢键网络在介导蛋白质-配体结合中起关键作用。计算结果表明，水分子的重新排列对结合亲和力有有利贡献，尽管其中一个水分子在从配体1变为配体2时被取代。另一个有利贡献来自配体2更大的蛋白质-配体相互作用。然而，这些有利贡献不足以克服复合物中配体2的不利去溶剂化自由能变化和羟丙基的构象熵，导致配体2的结合亲和力较低。这些物理见解可能有助于开发改进的结合亲和力预测评分函数。
