分子动力学模拟方法研究结构水在糖原合成酶激酶-3β中的作用

Molecular Dynamics Simulation of Significant Roles of Structural Water Molecules in Glycogen Synthase Kinase-3β

用分子动力学模拟的方法揭示了结构水分子在糖原合成酶激酶-3β(GSK-3β)中的作用.如果没有结构水,ATP嘌呤环的结合位置将发生偏移以填补结构水留下的空间;ATP结合口袋中的氢键网络将被破坏,保守残基Lys85与ATP的磷酸根侧链只能形成一个保守氢键,无法维持磷酸根转移所需的线性关系;由于失去了氢键网络的稳定作用,Glu97和Lys85会向远离ATP的方向移动,并导致Arg96的侧链发生偏转,使Arg96无法保持与Arg180和Lys205之间正常的相对位置,最终影响GSK-3β与底物的结合.

In this paper,we illustrate the significant role of structural water in GSK-3β using a dynamic simulation. We find that without structural water,the adenine moiety of ATP will drift from its correct position and prevent the formation of a H-bonding network. Conserved Lys85 can only form one H-bond with ATP and the in-line phosphoryl transfer mechanism would probably be destroyed. Glu97 and Lys85 are removed from ATP and the side chain of Arg96 will turn away,which can prevent substrate binding.