Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel

doi:10.1529/biophysj.103.039461

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel
	Yu, KQ; Fu, W ; Liu, H; Luo, XM; Chen, KX; Ding, JP ; Shen, JH
刊名	BIOPHYSICAL JOURNAL
	2004-06
卷号	86 期号:6 页码:3542-3555
ISSN号	0006-3495
DOI	10.1529/biophysj.103.039461
文献子类	Article
英文摘要	Based on a homology model of the Kv1.3 potassium channel, the recognitions of the six scorpion toxins, viz. agitoxin2, charybdotoxin, kaliotoxin, margatoxin, noxiustoxin, and Pandinus toxin, to the human Kv1.3 potassium channel have been investigated by using an approach of the Brownian dynamics (BD) simulation integrating molecular dynamics (MD) simulation. Reasonable three-dimensional structures of the toxin-channel complexes have been obtained employing BD simulations and triplet contact analyses. All of the available structures of the six scorpion toxins in the Research Collaboratory for Structural Bioinformatics Protein Data Bank determined by NMR were considered during the simulation, which indicated that the conformations of the toxin significantly affect both the molecular recognition and binding energy between the two proteins. BID simulations predicted that all the six scorpion toxins in this study use their beta-sheets to bind to the extracellular entryway of the Kv1.3 channel, which is in line with the primary clues from the electrostatic interaction calculations and mutagenesis results. Additionally, the electrostatic interaction energies between the toxins and Kv1.3 channel correlate well with the binding affinities (-logK(d)s), R-2 = 0.603, suggesting that the electrostatic interaction is a dominant component for toxin-channel binding specificity. Most importantly, recognition residues and interaction contacts for the binding were identified. Lys-27 or Lys-28, residues Arg-24 or Arg-25 in the separate six toxins, and residues Tyr-400, Asp-402, His-404, Asp-386, and Gly-380 in each subunit of the Kv1.3 potassium channel, are the key residues for the toxin-channel recognitions. This is in agreement with the mutation results. MD simulations lasting 5 ns for the individual proteins and the toxin-channel complexes in a solvated lipid bilayer environment confirmed that the toxins are flexible and the channel is not flexible in the binding. The consistency between the results of the simulations and the experimental data indicated that our three-dimensional models of the toxin-channel complex are reasonable and can be used as a guide for future biological studies, such as the rational design of the blocking agents of the Kv1.3 channel and mutagenesis in both toxins and the Kv1.3 channel. Moreover, the simulation result demonstrates that the electrostatic interaction energies combined with the distribution frequencies from BD simulations might be used as criteria in ranking the binding configuration of a scorpion toxin to the Kv1.3 channel.
WOS关键词	BROWNIAN DYNAMICS SIMULATIONS ; PARTICLE MESH EWALD ; SHAKER K+ CHANNELS ; HUMAN LYMPHOCYTE-T ; MOLECULAR-DYNAMICS ; STRUCTURAL DIFFERENCES ; NATURAL-PRODUCTS ; CHARYBDOTOXIN ; RECOGNITION ; PROTEINS
WOS研究方向	Biophysics
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000222035200016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274067]
专题	药物发现与设计中心
通讯作者	Ding, JP
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab New Drug Res, Ctr Drug Discovery & Design, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yu, KQ,Fu, W,Liu, H,et al. Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel[J]. BIOPHYSICAL JOURNAL,2004,86(6):3542-3555.
APA	Yu, KQ.,Fu, W.,Liu, H.,Luo, XM.,Chen, KX.,...&Shen, JH.(2004).Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel.BIOPHYSICAL JOURNAL,86(6),3542-3555.
MLA	Yu, KQ,et al."Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel".BIOPHYSICAL JOURNAL 86.6(2004):3542-3555.