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葡萄糖激酶(glucokinase,GK)催化葡萄糖转变为6-磷酸葡萄糖,是糖代谢的第一步,所以GK活性异常在糖代谢紊乱的发生发展中起着重要作用.对青年型早发糖尿病(maturity-onset diabetes of the young 2,MODY 2)型和高胰岛素性低血糖症(persistent hyperinsulinemic hypoglycemia of infancy,PHHI)型的深入研究证实了GK活性改变与糖尿病的发生有关.为了研究GK活性改变的机理,通过分子动力学模拟和隐性溶剂的自由能的计算对GK的单点突变M197V(Met197→Val)进行了理论研究.通过GK的Cα原子均方根浮动变化(Root mean square fluctuation,RMSF)和动态相关性矩阵(Dynamic cross-correlation matrices,DCCM)分析,显示M197V突变导致GK在活化状态的构象更加稳定.通过包结自由能分析,表明M197V突变可以增加GK对葡萄糖的包结亲合性,并且理论预测突变前后的相对包结自由能差值和已有的实验结果非常吻合.研究结果很好地从原子水平解释了GK的M197V突变的活化机理.
Glucokinase (GK) catalyzes the conversion of glucose into glucose 6-phosphate, which is the first step of glucose metabolism, so abnormal GK plays an important role in the occurrence and development of disorders of glucose metabolism.For maturity- onset diabetes of the young 2, MODY 2) and hyperinsulinemic hypoglycemia of infancy (PHHI) type, we found that the change of GK activity is related to the development of diabetes.In order to study the mechanism of the change of GK activity, The single point mutation M197V (Met197 → Val) of GK was studied theoretically by molecular dynamics simulation and calculation of the free energy of latent solvent.According to root mean square fluctuation (RMSF) of Cα of GK and Dynamic cross-correlation matrices (DCCM) analysis showed that the M197V mutation resulted in a more stable conformation of GK in the activated state.According to the analysis of entrapment free energy, it was shown that the M197V mutation increased the enthalpy of GK binding to glucose, and The theoretical predictions of the relative entanglement free energy before and after mutation are in good agreement with the existing experimental results.The results are well from the atomic level Explain the activation mechanism of the M197V mutation in GK.