Chen_2014_Protein.J_33_503

Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix alpha4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix alpha4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix alpha4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix alpha4, and elicited the large-scale conformational rearrangement of the helix alpha4, leading to the complete folding of the helix alpha4. Moreover, NEB simulations revealed that the conformational transition pathway of helix alpha4 underwent an almost 180 degrees counter-clockwise rotation of the helix alpha4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism.