Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer

doi:10.1016/j.bpj.2009.05.033

	Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer
	Gorfe, Alemayehu A.1; Lu, Benzhuo2 ; Yu, Zeyun 3; McCammon, J. Andrew 4
	2009-08-05
发表期刊	BIOPHYSICAL JOURNAL
ISSN	0006-3495
卷号	97 期号:3 页码:897-905
摘要	The function of many proteins, such as enzymes, is modulated by structural fluctuations. This is especially the case in gated diffusion-controlled reactions (where the rates of the initial diffusional encounter and of structural fluctuations determine the overall rate of the reaction) and in oligomeric proteins (where function often requires a coordinated movement of individual subunits). A classic example of a diffusion-controlled biological reaction catalyzed by an oligomeric enzyme is the hydrolysis of synaptic acetylcholine (ACh) by tetrameric acetylcholinesterase (AChEt). Despite decades of efforts, the extent to which enzymatic efficiency of AChEt (or any other enzyme) is modulated by flexibility is not fully determined. This article attempts to determine the correlation between the dynamics of AChEt and the rate of reaction between AChEt and ACh. We employed equilibrium and nonequilibrium electro-diffusion models to compute rate coefficients for an ensemble of structures generated by molecular dynamics simulation. We found that, for the static initial model, the average reaction rate per active site is similar to 22-30% slower in the tetramer than in the monomer. However, this effect of tetramerization is modulated by the intersubunit motions in the tetramer such that a complex interplay of steric and electrostatic effects either guides or blocks the substrate into or from each of the four active sites. As a result, the rate per active site calculated for some of the tetramer structures is only similar to 15% smaller than the rate in the monomer. We conclude that structural dynamics minimizes the adverse effect of tetramerization, allowing the enzyme to maintain similar enzymatic efficiency in different oligomerization states.
DOI	10.1016/j.bpj.2009.05.033
语种	英语
资助项目	National Science Foundation ; National Institutes of Health ; Howard Hughes Medical Institute ; National Biomedical Computation Resource ; Center for Theoretical Biological Physics ; 100 Talents Projects" of The Chinese Academy of Sciences
WOS研究方向	Biophysics
WOS类目	Biophysics
WOS记录号	WOS:000268926500024
出版者	CELL PRESS
引用统计
文献类型	期刊论文
条目标识符	http://ir.amss.ac.cn/handle/2S8OKBNM/8127
专题	计算数学与科学工程计算研究所
通讯作者	Gorfe, Alemayehu A.
作者单位	1.Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX USA 2.Chinese Acad Sci, Acad Math & Syst Sci, Inst Computat Math & Sci Engn Comp, Beijing, Peoples R China 3.Univ Wisconsin, Dept Comp Sci, Milwaukee, WI 53201 USA 4.Univ Calif San Diego, Dept Pharmacol, Howard Hughes Med Inst, Dept Chem & Biochem,Ctr Theoret Biol Phys, La Jolla, CA 92093 USA
推荐引用方式 GB/T 7714	Gorfe, Alemayehu A.,Lu, Benzhuo,Yu, Zeyun,et al. Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer[J]. BIOPHYSICAL JOURNAL,2009,97(3):897-905.
APA	Gorfe, Alemayehu A.,Lu, Benzhuo,Yu, Zeyun,&McCammon, J. Andrew.(2009).Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer.BIOPHYSICAL JOURNAL,97(3),897-905.
MLA	Gorfe, Alemayehu A.,et al."Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer".BIOPHYSICAL JOURNAL 97.3(2009):897-905.