title: Positive cooperative regulation of double binding sites for human acetylcholinesterase.
abstract: Acetylcholinesterase is a potent enzyme that regulates neurotransmission by rapidly hydrolyzing the neurotransmitter acetylcholine in synapses of the nervous system. As drug target of anti-AD, it has catalytic and peripheral anionic sites. However, the regulation relation between these two sites is unclear. Therefore, we constructed dynamics fluctuation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in double-site system (hAChE/TZ5) is distinctly different from that in the free state and single-site systems (hAChE/huprine and hAChE/1YL). The community network analysis indicates that the information freely transfers from the peripheral anionic site to the catalytic active site in hAChE/TZ5. Furthermore, the binding free energy between the inhibitor and hAChE for hAChE/TZ5 is significantly lower than of either hAChE/huprine or hAChE/1YL. Thus, a hypothesis of 'positive cooperative regulation' is proposed for the regulation of double binding sites and further confirmed by the weakening and mutation community analyses. Finally, one possible cooperative regulation pathway of W86-TZ5-W286 was identified based on the shortest path algorithm and was confirmed by the network perturbation analysis. Interestingly, the regulation pathway for single-site systems is significantly different from that of dual-site system. The process targeting on the shortest pathway can better regulate the hydrolyzing the neurotransmitter acetylcholine and significantly inhibit the aggregation of Aβ amyloid.
authors: State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.
authors: Hao
authors: H
authors: Liu
authors: State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.
authors: Wei
authors: W
authors: Ye
authors: State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.|Shanghai Center for Bioinformation Technology, Shanghai, China.
authors: Hai-Feng
authors: HF
authors: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
keywords: acetylcholinesterase; community; dynamics correlation network; positive cooperative regulation; regulation pathway