Molecular Dynamics Simulations On Structure And Functions Of Glycogen Synthesis Kinase-3?

Glycogen synthase kinase-3 (GSK-3) is a kind of serine-threonine protein kinase. GSK-3 is ubiquitously expressed in eukaryotes. There are two major isoforms of GSK-3 in mammals:GSK-3a and GSK-3?, which are encoded by different genes. It not only inactivates glycogen synthase (GS), but also places important roles in several signaling pathways, such as Insulin/IGF1 signaling pathways, Wnt/Shaggy signaling pathways, NGF signaling pathways, Estradiol signaling pathways, and the Reelin signaling pathway. GSK-3 (3 has more than 40 substrates. This makes it a key therapeutic target for a number of diseases, such as adult onset type 2 diabetes, stroke, neurodegenerative disorders (Alzheimer's disease), bipolar disorder, schizophrenia, acute inflammatory processes, cancer and so forth. According experimental studies and using dynamic simulations, this paper illustrates the effect of mutation K85R on GSK-3P, the significant roles of structure water molecules in GSK-3?, the probable mechanism of Li+inhibiting GSK-3?and the functions of structural metallic ions Mg2+.1. The conserved Lys85 is important to GSK-3?activity and in this paper we illustrate the significant role of Lys85 using dynamic simulation. We find that when Lys85 is mutated to Arg, one of the two conserved hydrogen bonds between Lys85 and ATP disappears, the salt bridge between Lys85 and Glu97 cannot form, and conformational changes of Phe93, Arg96 and Glu211 occur. These will cause conformational changes of the substrate binding groove that would inhibit the activity of GSK-3?. MM-GBSA calculations reveal that the K85R mutation could lead to a less energy-favorable complex, which is consistent with the structural analysis. This part illustrates the effect of mutation K85R on GSK-3?and provides more information about GSK-3?.2. We illustrate the significant role of structural water in GSK-3?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 move away from ATP and the side chain of Arg96 will turn away, which can prevent substrate binding. This part illustrates the important roles of structural waters in GSK-3?and proposes that when perform docking or dynamic simulations, the structural waters should be cautiously treated.3. Li+ is an inhibitor for GSK-3?. It is used to treat bipolar mood disorder. We illustrate the effect of Li+ on GSK-3?. Li+ is able to lower the atom fluctuation of GSK-3?systematically. When MgII is replaced by Li+, the in-line phosphoryl transfer mechanism is probably demolished and the binding of substrate would be disturbed. All the results we obtained clearly suggest that inhibition to GSK-3 is caused by the MgI replacement with Li+. This part proposes the probable mechanism of Li+ inhibiting GSK-3?and facilitates the further studies on effects of Li+.4. Mg2+ could stabilize the conformation of GSK-3?and ATP. Without Mg2+, the stabilization of GSK-3?explicitly reduces and conformation of ATP changes. MgI is more important in phosphorylation reaction, while MgII is not dispensable. Lysl83 alone is not competent for keeping conformation without the assistance of MgII. ATP would form intramolecular hydrogen bond and adopt folded conformation when two Mg2+ are absent. This part illustrates the effect of the Mg2+ on GSK-3?and provides more information about the functions of structural metallic ions in GSK-3 p.