發展金屬蛋白系統之新穎分子嵌合方法

Abstract

水分子與金屬離子在生物巨分子的結構或功能上扮演重要的角色。水分子可以與蛋白質或小分子形成氫鍵而介入其二者之間的交互作用，並且在許多研究報告當中指出，水分子在蛋白質與小分子的分子嵌合模擬當中具有巨大的影響力。因此在分子嵌合模擬方法的開發當中，如何適當地考慮水分子便成為一個相當重要的議題。 金屬離子如鋅、錳、鐵、銅在許多金屬蛋白中通常扮演著輔因子的角色，並且要使金屬蛋白的催化機轉得以正常運作，它們必須存在。在其他方面，金屬離子也可以穩定像蛋白質或核糖核酸等巨分子的結構，而使它們能夠正常地作用。許多金屬蛋白是重要的藥物作用標的，也因此使得在分子嵌合模擬當中能夠更適當地考慮金屬離子是必要的。然而，將小分子嵌入含有金屬離子的活性位置仍是一件具有相當挑戰性的工作。這是由於配位數的變異性、以及缺少可以精確描述小分子與金屬離子之間作用力的分子力場參數所致。 在此我們發展出一個具有一般性的方法，用在蛋白質與小分子的嵌合模擬中適當地考慮水分子，以及用電荷轉移效應來更精確地描述小分子與金屬離子之間的作用力，而非如一般分子嵌合方法中將電荷視為固定值。

Water and metal ions are important molecules that act structurally or functionally in macromolecules. Water molecules can be involved in the interaction between protein and ligand by forming hydrogen bonds, and many researches have been reported that sometimes they are crucial in docking studies. Therefore it makes the development of docking method which can consider water molecules explicitly to be an important issue. Metal ions, such like zinc, manganese, iron, and copper, are often act as metal cofactors in many metalloproteins and are crucial for their normal catalytic mechanism. In other cases, they can also stabilize the structure of macromolecules such as proteins or RNAs for normal function. Many metalloproteins are important drug targets, and hence there is a necessity to consider these metal ions more properly in molecular docking studies. However, docking ligands into metal-containing active site is still a challenging work because the varieties of coordination numbers and the lack of accurate force field parameters to describe the ligand-metal interaction. Here we develop a general method to consider the water explicitly, and at the same time the interaction between ligand and metal ions are considered more deliberately by introducing charge transfer effect in protein-ligand docking instead of static partial charges model in general docking methods.