Interaction simulation of hERG K+ channel with its specific BeKm-1 peptide: insights into the selectivity of molecular recognition

J Proteome Res. 2007 Feb;6(2):611-20. doi: 10.1021/pr060368g.

Abstract

Potassium channels show a huge variability in the affinity when recognizing enormous bioactive peptides, and the elucidation of their recognition mechanism remains a great challenge due to an undetermined peptide-channel complex structure. Here, we employed combined computation methods to study the specific binding of BeKm-1 peptide to the hERG potassium channel, which is an essential determinant 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. It has a "petunia" shape, while four "petals" of symmetrically distributed S5P segments always decentralize. Starting from the hERG and BeKm-1 structures, a considerably reasonable BeKm-1-hERG complex 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 complex was further assessed by computational alanine-scanning, with the results correlating reasonably well with experimental data. In the novel complex structure, four considerably flexible S5P linkers are far from the BeKm-1 peptide. The BeKm-1 mainly uses its helical region to associate the channel outer vestibule, except for the S5P linker region; however, structural analysis further implies this neutral pore region with wiggling S5P linker is highly beneficial to the binding of BeKm-1 with lower positive charges. The most critical Lys18 of BeKm-1 plugs its side chain into the channel selectivity filter, while the secondarily important Arg20 forms three hydrogen bonds with spatially neighboring residues in the hERG channel. Different from the classical peptide-K+ channel interaction mainly induced by electrostatic interaction, a synergetic effect of the electrostatic and van der Waals interactions was found to mediate the molecular recognition between BeKm-1 and the hERG channel. And this specific binding process is revealed to be a dynamic change of reduction of binding free energy and conformational rearrangement mainly in the interface of both BeKm-1 and the hERG channel. All these structural 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 important clues to further study structure-function relationships of the hERG channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation
  • Ether-A-Go-Go Potassium Channels / chemistry*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptides / pharmacology
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology
  • Protein Conformation
  • Scorpion Venoms / chemistry*
  • Scorpion Venoms / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid

Substances

  • BeKm-1 toxin
  • Ether-A-Go-Go Potassium Channels
  • Peptide Fragments
  • Peptides
  • Potassium Channel Blockers
  • Scorpion Venoms