桑色素与基质金属蛋白酶中催化锌离子相互作用机理的理论研究

Theoretical Studies on the Mechanisms of Interaction between Morin and the Catalytic Zinc Ion in Matrix Metalloproteinases

运用PM6量子化学计算方法,并通过设计配体交换反应,研究了桑色素与基质金属蛋白酶(MMPs)中催化锌离子(Zn2+)的相互作用机理.研究发现,当桑色素分子中A,B,C环上不同部位的基团与MMPs中催化锌离子络合时,发生了电子从桑色素分子向催化锌离子的转移,且电子转移越多,越有利于增强它们之间的络合能力.进一步研究发现,在桑色素分子的不同部位基团中,以4位羰基的氧原子与MMPs中催化锌离子的络合能力最强,这表明桑色素应主要通过其4位羰基对MMPs产生抑制作用,而不是其它部位的羟基.回归分析结果显示,计算得到的6个配体交换反应的自由能变化(?G298)与反应生成的各络离子中的Zn—O键长、桑色素分子的总原子电荷以及配位O原子的电荷之间均存在着较好的线性相关性.我们的计算结果与文献中相关的实验和理论结果一致.有关作用机理的研究结果可为将来通过对桑色素分子进行结构修饰、以设计出生物活性有显著提高的MMPs抑制剂提供重要参考.

The mechanisms of interaction between morin and the catalytic zinc ion （Zn^2＋） in matrix metal- loproteinases （MMPs） are investigated by using PM6 quantum chemistry method and designing ligand-exchange reactions. It is found that the electron transfer from morin molecule to catalytic zinc ion occurs when the groups at the various positions of A, B and C rings of morin molecule coordinate with cata- lytic zinc ion in MMPs, and the more the electron transfer, the stronger coordinating ability between them. We further find that among the groups at the various positions of morin molecule, the coordinating ability between the oxygen atom of the carbonyl group at the 4-position and catalytic zinc ion is the strongest, which indicates that the inhibition of MMPs activities is produced mainly by the carbonyl group at the 4-position of morin, rather than the hydroxy groups at the other positions. Regression analysis show that there are better linear relationships between the calculated free energy changes （AG298） for the 6 ligand-exchange reactions and the Zn--O bond length, total atomic charges in the morin molecule, and the charges of coordinating 0 atoms in the produced coordinating ions. Our calculated results are in agreement with available experimental and theoretical results. These results of the interaction mechanisms may provide important reference data for the structural modifications of the morin molecule to design the MMPs inhibitors whose biological activities can obviously be improved.