Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C-60 Nanoparticles via in Vitro and in Silico Assays

CORC > 生态环境研究中心 > 中国科学院生态环境研究中心 > 环境化学与生态毒理学国家重点实验室

	Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C-60 Nanoparticles via in Vitro and in Silico Assays
	Liu, Yanyan; Yan, Bing; Winkler, David A.; Fu, Jianjie; Zhang, Aigian
刊名	ACS APPLIED MATERIALS & INTERFACES
	2017-05-10
卷号	9 期号:22 页码:18626-18638
关键词	C-60 Nanoparticle Acetylcholinesterase Competitive Inhibition Peripheral Anionic Site Quantitative Nanostructure-activity Relationship Molecular Docking Site-directed Mutation
英文摘要	Acetylcholinesterase (AChE) activity regulation by chemical agents or, potentially, nanomaterials is important for both toxicology and pharmacology. Competitive inhibition via direct catalytic active sites (CAS) binding or noncompetitive inhibition through interference with substrate and product entering and exiting has been recognized previously as an AChE-inhibition mechanism for bespoke nanomaterials. The competitive inhibition by peripheral anionic site (PAS) interaction without CAS binding remains unexplored. Here, we proposed and verified the occurrence of a presumed competitive inhibition of AChE without CAS binding for hydrophobically functionalized C-60 nano particles (NPs) by employing both experimental and computational methods. The kinetic inhibition analysis distinguished six competitive inhibitors, probably targeting the PAS from the pristine and hydrophilically modified C-60 NPs. A simple quantitative nanostructure activity relationship (QNAR) model relating the pocket accessible length of substituent to inhibition capacity was then established to reveal how the geometry of the:surface group decides. the NP difference in AChE inhibition. Molecular docking identified the PAS as the potential binding site interacting with the NPs via a T-shaped plug-in mode. Specifically, the fullerene core covered the enzyme gorge as a lid through pi-pi stacking with Tyr72 and Trp286 in the PAS, while the hydrophobic ligands on the fullerene surface inserted into the AChE active site to provide further stability for the complexes. The modeling predicted that :inhibition would be severely compromised by Tyr72 and Trp286 deletions, and the subsequent site-directed mutagenesis experiments proved this prediction. Our results demonstrate AChE competitive inhibition of NPs without CAS partidpatidn to fnrther understanding of both the neurotoxicity and the curative effect of NPs.
内容类型	期刊论文
源URL	[http://ir.rcees.ac.cn/handle/311016/39277]
专题	生态环境研究中心_环境化学与生态毒理学国家重点实验室
推荐引用方式 GB/T 7714	Liu, Yanyan,Yan, Bing,Winkler, David A.,et al. Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C-60 Nanoparticles via in Vitro and in Silico Assays[J]. ACS APPLIED MATERIALS & INTERFACES,2017,9(22):18626-18638.
APA	Liu, Yanyan,Yan, Bing,Winkler, David A.,Fu, Jianjie,&Zhang, Aigian.(2017).Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C-60 Nanoparticles via in Vitro and in Silico Assays.ACS APPLIED MATERIALS & INTERFACES,9(22),18626-18638.
MLA	Liu, Yanyan,et al."Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C-60 Nanoparticles via in Vitro and in Silico Assays".ACS APPLIED MATERIALS & INTERFACES 9.22(2017):18626-18638.