Paper Report for: Cheng_2007_J.Am.Chem.Soc_129_6562
Reference
Title: Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses Cheng Y, Cheng X, Radic Z, McCammon JA Ref: Journal of the American Chemical Society, 129:6562, 2007 : PubMed
The reaction mechanisms of two inhibitors TFK+ and TFK0 binding to both the wild-type and H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. In the wild-type mAChE, the binding reactions of TFK+ and TFK0 are both spontaneous processes, which proceed through the nucleophilic addition of the Ser203-Ogamma to the carbonyl-C of TFK+ or TFK0, accompanied with a simultaneous proton transfer from Ser203 to His447. No barrier is found along the reaction paths, consistent with the experimental reaction rates approaching the diffusion-controlled limit. By contrast, TFK+ binding to the H447I mutant may proceed with a different reaction mechanism. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8 kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK0, however, multiple MD simulations on the TFK0/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Furthermore, our alchemical free energy calculation also suggests that the binding of TFK0 to H447I is much weaker than that of TFK+. Taken together, our computational studies confirm that TFK0 is almost inactive in the H447I mutant and also provide detailed mechanistic insights into the experimental observations.
        
Related information
Citations formats
Cheng Y, Cheng X, Radic Z, McCammon JA (2007) Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses Journal of the American Chemical Society129: 6562-70
Cheng Y, Cheng X, Radic Z, McCammon JA (2007) Journal of the American Chemical Society129: 6562-70