Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b(562)

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	Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b(562)
	Duan, Mojie 1,2; Liu, Hanzhong 1; Li, Minghai 1; Huo, Shuanghong 1
刊名	JOURNAL OF CHEMICAL PHYSICS
	2015-10-07
卷号	143 期号:13
英文摘要	The folding kinetics of Rd-apocytochrome b(562) is two-state, but native-state hydrogen exchange experiments show that there are discrete partially unfolded (PUF) structures in equilibrium with the native state. These PUF structures are called hidden intermediates because they are not detected in kinetic experiments and they exist after the rate-limiting step. Structures of the mimics of hidden intermediates of Rd-apocytochrome b(562) are resolved by NMR. Based upon their relative stability and structural features, the folding mechanism was proposed to follow a specific pathway (unfolded -> rate-limiting transition state -> PUF1 -> PUF2 -> native). Investigating the roles of equilibrium PUF structures in folding kinetics and their interrelationship not only deepens our understanding of the details of folding mechanism but also provides guides in protein design and prevention of misfolding. We performed molecular dynamics simulations starting from a hidden intermediate and the native state of Rd-apocytochrome b(562) in explicit solvent, for a total of 37.18 mu s mainly with Anton. We validated our simulations by detailed comparison with experimental data and other computations. We have verified that we sampled the post rate-limiting transition state region only. Markov state model was used to analyze the simulation results. We replace the specific pathway model with a network model. Transition-path theory was employed to calculate the net effective flux from the most unfolded state towards the most folded state in the network. The proposed sequential folding pathway via PUF1 then more stable, more native-like PUF2 is one of the routes in our network, but it is not dominant. The dominant path visits PUF2 without going through PUF1. There is also a route from PUF1 directly to the most folded state in the network without visiting PUF2. Our results indicate that the PUF states are not necessarily sequential in the folding. The major routes predicted in our network are testable by future experiments such as single molecule experiment. (C) 2015 AIP Publishing LLC.
WOS标题词	Science & Technology ; Physical Sciences
类目[WOS]	Physics, Atomic, Molecular & Chemical
研究领域[WOS]	Physics
关键词[WOS]	STATE HYDROGEN-EXCHANGE ; NONNATIVE HYDROPHOBIC INTERACTIONS ; EXPLORING SUBDOMAIN COOPERATIVITY ; 4-HELIX BUNDLE PROTEIN ; FOLDING INTERMEDIATE ; MOLECULAR-DYNAMICS ; SEQUENTIAL STABILIZATION ; ATOMIC-RESOLUTION ; PATHWAYS ; KINETICS
收录类别	SCI
语种	英语
WOS记录号	WOS:000362669400048
公开日期	2015-11-17
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/8194]
专题	武汉物理与数学研究所_理论与交叉研究部
作者单位	1.Clark Univ, Gustaf H Carlson Sch Chem & Biochem, Worcester, MA 01610 USA 2.Chinese Acad Sci, Wuhan Inst Phys & Math, Natl Ctr Magnet Resonance Wuhan,Key Lab Magnet Re, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan 430071, Peoples R China
推荐引用方式 GB/T 7714	Duan, Mojie,Liu, Hanzhong,Li, Minghai,et al. Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b(562)[J]. JOURNAL OF CHEMICAL PHYSICS,2015,143(13).
APA	Duan, Mojie,Liu, Hanzhong,Li, Minghai,&Huo, Shuanghong.(2015).Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b(562).JOURNAL OF CHEMICAL PHYSICS,143(13).
MLA	Duan, Mojie,et al."Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b(562)".JOURNAL OF CHEMICAL PHYSICS 143.13(2015).