分子动力学模拟研究活化剂对葡萄糖激酶活性的影响及活化机理

葡萄糖激酶(GK)催化葡萄糖转变为6-磷酸葡萄糖,是糖代谢的第一步;GK的活性改变对葡萄糖的代谢影响很大.通过分子动力学模拟研究了葡萄糖激酶活化剂(GKA)对GK活性的影响,探讨了GKA的活化机理.包结自由能分析表明,范德华作用是GK和GKA体系的主要驱动力;与此同时,葡萄糖使得GK和GKA的结合增强.构象分析结果表明,GKA能够在一段时间内限制GK的构象,但不能长久维持GK的活化构象不变,这和以往的实验结果相一致.相关理论分析结果不仅有利于从原子水平解释GKA的活化机理,也可为设计新的用于糖尿病治疗的GKA提供一定的理论参考.

Effect of activator on activity of glucokinase and activation mechanism of the activator-study by molecular dynamics simulation

Glucokinase（GK） is a glycolic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate in the first step of glycolysis,and the change in GK activity plays an important role in abnormal glycemia.Thus molecular dynamics simulation was performed to study the effect of glucokinase activator（GKA） on the activity of GK,and the activation mechanism of GKA was examined.The binding free-energy analysis suggests that van der Walls forces are the main driving forces for GK-GKA complex,and glucose can enhance the binding between GK and GKA.Moreover,conformation analysis shows that GKA can constrain the conformation of GK in a period of time,but it cannot keep the active state of GK in an extended period,which is in agreement with previously reported experiment results.These observations are beneficial to understanding the activation mechanism of GKA at an atomic level and to guiding the design of novel GKA for the treatment of diabetes.