| Abstract
| - The entering and leaving processes of Huperzine A (HupA) binding with the long active-sitegorge of Torpedo californica acetylcholinesterase (TcAChE) have been investigated by using steeredmolecular dynamics simulations. The analysis of the force required along the pathway shows that it iseasier for HupA to bind to the active site of AChE than to disassociate from it, which for the first timeinterprets at the atomic level the previous experimental result that unbinding process of HupA is muchslower than its binding process to AChE. The direct hydrogen bonds, water bridges, and hydrophobicinteractions were analyzed during two steered molecular dynamics (SMD) simulations. Break of the directhydrogen bond needs a great pulling force. The steric hindrance of bottleneck might be the most importantfactor to produce the maximal rupture force for HupA to leave the binding site but it has a little effect on thebinding process of HupA with AChE. Residue Asp72 forms a lot of water bridges with HupA leaving andentering the AChE binding gorge, acting as a clamp to take out HupA from or put HupA into the active site.The flip of the peptide bond between Gly117 and Gly118 has been detected during both the conventionalMD and SMD simulations. The simulation results indicate that this flip phenomenon could be an intrinsicproperty of AChE and the Gly117−Gly118 peptide bond in both HupA bound and unbound AChE structurestends to adopt the native enzyme structure. At last, in a vacuum the rupture force is increased up to 1500pN while in water solution the greatest rupture force is about 800 pN, which means water molecules in thebinding gorge act as lubricant to facilitate HupA entering or leaving the binding gorge.
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