Constrained proper sampling of conformations of transition state ensemble of protein folding

CORC > 厦门大学 > 化学化工－已发表论文

	Constrained proper sampling of conformations of transition state ensemble of protein folding
	Lin, Ming ; Zhang, Jian ; Lu, Hsiao-Mei ; Chen, Rong ; Liang, Jie ; Lin M(林敏)
刊名	http://dx.doi.org/10.1063/1.3519056
	2011-02-21
关键词	MOLECULAR-DYNAMICS CONTACT SIMULATIONS PATHWAYS SEQUENCE BINDING TOPOLOGY ENERGY DOMAIN RATES
英文摘要	NIH [GM079804, GM081682]; NSF [DBI-0646035, DMS-0800257, DMS-0800183, DMS-0915139, DMS-0905763]; Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo et al. [Nature (London) 409, 641 (2001)] to study TSE is to generate conformations that satisfy all constraints imposed by the experimentally measured phi values that provide information about the native likeness of the transition states. Faisca et al. [J. Chem. Phys. 129, 095108 (2008)] generated conformations of TSE based on the criterion that, starting from a TS conformation, the probabilities of folding and unfolding are about equal through Markov Chain Monte Carlo (MCMC) simulations. In this study, we use the technique of constrained sequential Monte Carlo method [Lin et al., J. Chem. Phys. 129, 094101 (2008); Zhang et al. Proteins 66, 61 (2007)] to generate TSE conformations of acylphosphatase of 98 residues that satisfy the phi-value constraints, as well as the criterion that each conformation has a folding probability of 0.5 by Monte Carlo simulations. We adopt a two stage process and first generate 5000 contact maps satisfying the phi-value constraints. Each contact map is then used to generate 1000 properly weighted conformations. After clustering similar conformations, we obtain a set of properly weighted samples of 4185 candidate clusters. Representative conformation of each of these cluster is then selected and 50 runs of Markov chain Monte Carlo (MCMC) simulation are carried using a regrowth move set. We then select a subset of 1501 conformations that have equal probabilities to fold and to unfold as the set of TSE. These 1501 samples characterize well the distribution of transition state ensemble conformations of acylphosphatase. Compared with previous studies, our approach can access much wider conformational space and can objectively generate conformations that satisfy the phi-value constraints and the criterion of 0.5 folding probability without bias. In contrast to previous studies, our results show that transition state conformations are very diverse and are far from nativelike when measured in cartesian root-mean-square deviation (cRMSD): the average cRMSD between TSE conformations and the native structure is 9.4 angstrom for this short protein, instead of 6 angstrom reported in previous studies. In addition, we found that the average fraction of native contacts in the TSE is 0.37, with enrichment in native-like beta-sheets and a shortage of long range contacts, suggesting such contacts form at a later stage of folding. We further calculate the first passage time of folding of TSE conformations through calculation of physical time associated with the regrowth moves in MCMC simulation through mapping such moves to a Markovian state model, whose transition time was obtained by Langevin dynamics simulations. Our results indicate that despite the large structural diversity of the TSE, they are characterized by similar folding time. Our approach is general and can be used to study TSE in other macromolecules. (C) 2011 American Institute of Physics. [doi:10.1063/1.3519056]
语种	英语
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/62450]
专题	化学化工－已发表论文
推荐引用方式 GB/T 7714	Lin, Ming,Zhang, Jian,Lu, Hsiao-Mei,et al. Constrained proper sampling of conformations of transition state ensemble of protein folding[J]. http://dx.doi.org/10.1063/1.3519056,2011.
APA	Lin, Ming,Zhang, Jian,Lu, Hsiao-Mei,Chen, Rong,Liang, Jie,&林敏.(2011).Constrained proper sampling of conformations of transition state ensemble of protein folding.http://dx.doi.org/10.1063/1.3519056.
MLA	Lin, Ming,et al."Constrained proper sampling of conformations of transition state ensemble of protein folding".http://dx.doi.org/10.1063/1.3519056 (2011).