Glucokinase (GK) is a glycolic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate in the first step of glycolysis. Thus alteration in GK activity plays an important role in abnormal glycemia. A great deal of research about maturity-onset diabetes of the young 2 (MODY 2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) confirmed that the change of GK activity was associated with diabetes. The explicit molecular dynamics simulations and implicit solvent binding free-energy calculations were investigated to understand the activation mechanism of GK point mutation M197V (Met¹⁹⁷ →Val). The root mean square fluctuation (RMSF) and dynamic cross-correlation matrices (DCCM) conformation analysis showed that GK M197V mutation resulted in a more stable active conformation. The binding free-energy analysis demonstrated that the GK M197V mutation increased its binding affinity with glucose. The difference of binding free-energy between wild-type (WT) GK and M197V GK was in well agreement with previous experimental results. Our results can interpret the active mechanism of GK M197V mutation from the atom level perfectly.

Key words: glucokinase, molecular dynamics, DCCM, MM-PBSA