Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase

	Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase
	Palla, M; Chen, CP; Zhang, Y; Li, JY; Ju, JY; Liao, JC;李敬源
刊名	JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
	2013
卷号	31 期号:2 页码:129-141
关键词	molecular dynamics simulation ATP-binding cleft pairwise distance analysis RMSF analysis hinge motion
英文摘要	Hepatitis C virus (HCV) NS3 helicase couples adenosine triphosphate (ATP) binding and hydrolysis to polynucleotide unwinding. Understanding the regulation mechanism of ATP binding will facilitate targeting of the ATP-binding site for potential therapeutic development for hepatitis C. T324, an amino acid residue connecting domains 1 and 2 of NS3 helicase, has been suggested as part of a flexible hinge for opening of the ATP-binding cleft, although the detailed mechanism remains largely unclear. We used computational simulation to examine the mutational effect of T324 on the dynamics of the ATP-binding site. A mutant model, T324A, of the NS3 helicase apo structure was created and energy was minimized. Molecular dynamics simulation was conducted for both wild type and the T324A mutant apo structures to compare their differences. For the mutant structure, histogram analysis of pairwise distances between residues in domains 1 and 2 (E291-Q460, K210-R464 and R467-T212) showed that separation between the two domains was reduced by 10% and the standard deviation by 33%. Root mean square fluctuation (RMSF) analysis demonstrated that residues in close proximity to residue 324 have at least 30% RMSF value reductions in the mutant structure. Solvent RMSF analysis showed that more water molecules were trapped near D290 and H293 in domain 1 to form an extensive interaction network constraining cleft opening. We also demonstrated that the T324A mutation established a new atomic interaction with V331, revealing that an atomic interaction cascade from T324 to residues in domains 1 and 2 controls the flexibility of the ATP-binding cleft.
学科主题	Biochemistry & Molecular Biology; Biophysics
收录类别	SCI
WOS记录号	WOS:000313642100001
公开日期	2016-05-03
内容类型	期刊论文
源URL	[http://ir.ihep.ac.cn/handle/311005/223859]
专题	中国科学院高能物理研究所
推荐引用方式 GB/T 7714	Palla, M,Chen, CP,Zhang, Y,et al. Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase[J]. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2013,31(2):129-141.
APA	Palla, M,Chen, CP,Zhang, Y,Li, JY,Ju, JY,&Liao, JC；李敬源.(2013).Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase.JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,31(2),129-141.
MLA	Palla, M,et al."Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase".JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 31.2(2013):129-141.