Interaction Simulation of hERG K+ Channel with Its Specific BeKm-1 Peptide: Insights into the Selectivity of Molecular Recognition
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- 作者：Hong Yi ; Zhijian Cao ; Shijin Yin ; Chao Dai ; Yingliang Wu ; Wenxin Li
- 刊名：Journal of Proteome Research
- 出版年：2007
- 出版时间：February 2007
- 年：2007
- 卷：6
- 期：2
- 页码：611 - 620
- 全文大小：930K
- 年卷期：v.6,no.2(February 2007)
- ISSN：1535-3907
文摘
Potassium channels show a huge variability in the affinity when recognizing enormous bioactivepeptides, and the elucidation of their recognition mechanism remains a great challenge due to anundetermined peptide-channel complex structure. Here, we employed combined computation methodsto study the specific binding of BeKm-1 peptide to the hERG potassium channel, which is an essentialdeterminant of the long-QT syndrome. By the use of a segment-assembly homology modeling method,the closed-state hERG structure containing unusual longer S5P linker was successfully constructed. Ithas a "petunia" shape, while four "petals" of symmetrically distributed S5P segments alwaysdecentralize. Starting from the hERG and BeKm-1 structures, a considerably reasonable BeKm-1-hERGcomplex structure was then screened out and identified by protein-protein docking, molecular dynamics(MD) simulations, and calculation of relative binding free energies. The validity of this predicted complexwas further assessed by computational alanine-scanning, with the results correlating reasonably wellwith experimental data. In the novel complex structure, four considerably flexible S5P linkers are farfrom the BeKm-1 peptide. The BeKm-1 mainly uses its helical region to associate the channel outervestibule, except for the S5P linker region; however, structural analysis further implies this neutralpore region with wiggling S5P linker is highly beneficial to the binding of BeKm-1 with lower positivecharges. The most critical Lys18 of BeKm-1 plugs its side chain into the channel selectivity filter, whilethe secondarily important Arg20 forms three hydrogen bonds with spatially neighboring residues inthe hERG channel. Different from the classical peptide-K+ channel interaction mainly induced byelectrostatic interaction, a synergetic effect of the electrostatic and van der Waals interactions wasfound to mediate the molecular recognition between BeKm-1 and the hERG channel. And this specificbinding process is revealed to be a dynamic change of reduction of binding free energy andconformational rearrangement mainly in the interface of both BeKm-1 and the hERG channel. All thesestructural and energy features yield deep insights on the high selective binding mechanism of hERG-specific peptides, present a diversity of peptide-K+ channel interactions, and also provide importantclues to further study structure-function relationships of the hERG channel.