Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels

	Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels
	Cui, M; Shen, JH; Briggs, JM; Fu, W; Wu, JL; Zhang, YM; Luo, XM; Chi, ZW; Ji, RY; Jiang, HL
刊名	JOURNAL OF MOLECULAR BIOLOGY
	2002
卷号	318 期号:2 页码:417-428
关键词	molecular modeling Brownian dynamics molecular recognition electrostatic steering potassium channels
通讯作者	Jiang, HL (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Meteria Med, Ctr Drug Discovery & Design,State Key Lab Drug Res, 294 Taiyuan Rd, Shanghai 200031, Peoples R China.,
英文摘要	The recognition of the scorpion toxin P05 and the small-conductance, calcium-activated potassium (SK) channels, rsk1, rsk2, and rsk3, has been studied by means of the Brownian dynamics (BD) method. All of the 25 available structures of P05 in the RCSB Protein Data Bank determined by NMR were considered during the simulation, which indicated that the conformation of P05 affects both the recognition and binding between the two proteins significantly. Comparing the top four high-frequency structures of P05 binding to the SK channels, we found that the rsk2 channel, with high frequencies and lowest electrostatic interaction energies (E-int(ES)), is the most favorable for P05 binding, while rsk3 is intermediate, and rsk1 is the least favorable. Among the 25 structures of P05, the 13th structure docks into the binding site of the rsk2 channel with the highest probability and most favorable electrostatic interactions. From the P05-rsk2 channel binding model, we identified the residues critical for the recognition of these two proteins through triplet contact analyses. P05 locates around the extracellular mouth of the SK channels and contacts the SK channels using its alpha-helix rather than beta-sheets. The critical triplet contacts for recognition between P05 and the rsk2 channel are Arg6 (P05)-Asp364 (SK), Arg7 (P05)-Asn368 (SK), and Arg13 (P05)-Asp341 (SK). The structure of the P05-rsk2 complex with the most favorable electrostatic interaction energy was further refined by molecular mechanics, showing that six hydrogen bonding interactions exist between P05 and the rsk2 channel: one hydrogen bond is formed between Arg6 (P05) and Asp364(D) (rsk2); Arg7 (P05) forms three hydrogen bonds with Asp341(B) (rsk2)) and Asp364(C) (rsk2); two hydrogen bonds are formed by Arg13 (P05) with Asp341(A) (rsk2) and Asp364(B) (rsk2). The simulation results are in good agreement with the previous molecular biological experiments and can explain the binding phenomena between P05 and SK channels at the level of molecular structure. The consistency between the results of the BD simulations and the experimental data indicated that our 3D model of the P05-rsk2 channel complex is reasonable and can be employed in further biological studies, such as rational design of the novel therapeutic agents blocking the small-conductance, calcium-activated and apamin-sensitive potassium channels, and for mutagenesis studies in both toxins and SK channels. In particular, both the BD simulations and the molecular mechanics refinements indicate that residue Asp364 of the rsk2 channel is critical for its recognition and binding functionality towards P05. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating that this might be a new clue for further functional study of SK channels. (C) 2002 Elsevier Science Ltd. All rights reserved.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	LEIURUS-QUINQUESTRIATUS VENOM ; CA2+-ACTIVATED K+ CHANNELS ; NUCLEAR MAGNETIC-RESONANCE ; APAMIN ; PROTEINS ; ASSOCIATION ; AFFINITY ; BINDING ; PROGRAM ; ANALOG
收录类别	SCI
语种	英语
WOS记录号	WOS:000175479300017
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2440]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Cui, M,Shen, JH,Briggs, JM,et al. Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels[J]. JOURNAL OF MOLECULAR BIOLOGY,2002,318(2):417-428.
APA	Cui, M.,Shen, JH.,Briggs, JM.,Fu, W.,Wu, JL.,...&Chen, KX.(2002).Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels.JOURNAL OF MOLECULAR BIOLOGY,318(2),417-428.
MLA	Cui, M,et al."Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels".JOURNAL OF MOLECULAR BIOLOGY 318.2(2002):417-428.