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	Molecular Dynamics Simulations of the Detoxification of Paraoxon Catalyzed by Phosphotriesterase
	Zhang, Xin ; Wu, Ruibo ; Song, Lingchun ; Lin, Yuchun（ Western Michigan Univ, Dept Chem） ; Lin, Menghai ; Lin MH(林梦海) ; Cao, Zexing ; Cao ZX(曹泽星) ; Wu, Wei ; Wu W(吴玮) ; Mo, Yirong
	2009-04
关键词	combined QM/MM molecular dynamics simulation phosphotriesterase paraoxon detoxification
英文摘要	Combined QM(PM3)/MM molecular dynamics simulations together with QM(DFT)/MM optimizations for key configurations have been performed to elucidate the enzymatic catalysis mechanism on the detoxification of paraoxon by phosphotriesterase (PTE). In the simulations, the PM3 parameters for the phosphorous atom were reoptimized. The equilibrated configuration of the enzyme/substrate complex showed that paraoxon can strongly bind to the more solvent-exposed metal ion Zn-beta, but the free energy profile along the binding path demonstrated that the binding is thermodynamically unfavorable. This explains why the crystal structures of PTE with substrate analogues often exhibit long distances between the phosphoral oxygen and Zn-beta. The subsequent S(N)2 reaction plays the key role in the whole process, but controversies exist over the identity of the nucleophilic species, which could be either a hydroxide ion terminally coordinated to Zn-alpha or the mu-hydroxo bridge between the alpha a- and beta-metals. Our simulations supported the latter and showed that the rate-limiting step is the distortion of the bound paraoxon to approach the bridging hydroxide. After this preparation step, the bridging hydroxide ion attacks the phosphorous center and replaces the diethyl phosphate with a low barrier. Thus, a plausible way to engineer PTE with enhanced catalytic activity is to stabilize the deformed paraoxon. Conformational analyses indicate that Trp131 is the closest residue to the phosphoryl oxygen, and mutations to Arg or Gln or even Lys, which can shorten the hydrogen bond distance with the phosphoryl oxygen, could potentially lead to a mutant with enhanced activity for the detoxification of organo-phosphates. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 30: 2388-2401, 2009; The Keck foundation ; The National Institute of Health (NTH) ; Faculty Research and Creative Activities ; Western Michigan University
语种	英语
出版者	JOHN WILEY & SONS INC
内容类型	期刊论文
源URL	[http://dx.doi.org/doi:10.1002/jcc.21238]
专题	化学化工－已发表论文
推荐引用方式 GB/T 7714	Zhang, Xin,Wu, Ruibo,Song, Lingchun,et al. Molecular Dynamics Simulations of the Detoxification of Paraoxon Catalyzed by Phosphotriesterase[J],2009.
APA	Zhang, Xin.,Wu, Ruibo.,Song, Lingchun.,Lin, Yuchun.,Lin, Menghai.,...&Mo, Yirong.(2009).Molecular Dynamics Simulations of the Detoxification of Paraoxon Catalyzed by Phosphotriesterase..
MLA	Zhang, Xin,et al."Molecular Dynamics Simulations of the Detoxification of Paraoxon Catalyzed by Phosphotriesterase".(2009).

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