In Silico Observation of the Conformational Opening of the Glutathione-Binding Site of Microsomal Prostaglandin E2 Synthase-1.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is known as an ideal target for next-generation anti-inflammatory drugs to effectively and safely treat a variety of inflammation-related diseases. High-resolution X-ray crystal structures are available for human mPGES-1, but all in a closed conformation for a glutathione (GSH)-binding site. Here, we report an in silico observation of the desirable open conformation of mPGES-1 using a simple computational strategy with fully relaxed molecular dynamics simulations starting a high-resolution X-ray crystal structure in the closed conformation. The open conformation mainly exists in the apo-form. Once GSH enters the binding site, the binding site is closed and, thus, mPGES-1 becomes the closed conformation. According to the determined free energy profile, both the open and closed conformations can co-exist in solution with a thermodynamic equilibrium, and the conformational distribution is dependent on the GSH concentration. In addition, the cap domain responsible for the conformational transition is located right on the crystal packing interface, showing that only closed conformation is suitable for the crystal packing. All of the computational insights are consistent with reported experimental observations. The computationally simulated open conformation of mPGES-1 may serve as a new target state for the rational design of novel inhibitors of mPGES-1. We anticipate that a computational strategy similar to the one used in this study may also be used to explore open conformation starting from a crystal structure of the corresponding closed conformation with a ligand bound for other proteins.