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Molecular basis of inhibitory peptide maurotoxin recognizing Kv1.2 channel explored by ZDOCK and molecular dynamic simulations
Author(s) -
Yi Hong,
Qiu Su,
Cao Zhijian,
Wu Yingliang,
Li Wenxin
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21706
Subject(s) - chemistry , molecular dynamics , peptide , docking (animal) , energy minimization , stereochemistry , side chain , molecular model , binding site , interaction energy , computational chemistry , biophysics , crystallography , molecule , biochemistry , medicine , nursing , organic chemistry , biology , polymer
Inhibitory peptide‐channel interactions have been utilized to characterize both channels and peptides; however, the fundamental basis for these interactions remains elusive. Here, combined computation methods were employed to study the specific binding of maurotoxin (MTX) peptide to Kv1.2 channel. In the first stage, numerous predicted complexes were generated by docking an ensemble of all 35 NMR conformations of MTX to Kv1.2 channel with ZDOCK program. Then the resulted complexes were clustered and classified into four main binding modes, based on experimental information and interaction energy analysis after the energy minimization and molecular dynamics (MD) simulations. By examining the stability of the plausible candidates through unrestrained MD simulations and calculation of the binding free energies, a final reasonable MTX‐Kv1.2 complex was identified, with an overall high degree of correlation between the calculation and experiment on mutational effects. In the obtained complex structure model, MTX mainly used its β‐sheet domains to associate the channel mouth instead of the well‐recognized functionally important S5P linkers of Kv1.2 channel. Structure analysis characterized that the most essential Tyr 32 residue of MTX was surrounded by a “pocket” formed by many nonpolar and polar residues of Kv1.2 channel, and revealed a pore‐blocking Lys 23 and an important Lys 7 stabilized by strong electrostatic interactions with Asp 379 of Kv1.2. Furthermore, a stepwise structural arrangement for both ligand and receptor was found to accompany the tighter interaction of MTX into the target channel. The starting conformation of MTX, the side‐chain conformation of the most important residue Tyr 32 , and proper introduction of flexibility for candidate complexes were demonstrated to be considerably important factors for obtaining the final reasonable complex structure model. All these findings should not only be helpful for identifying more plausible K + channel‐inhibitory peptide complex structures, but also provide intrinsically valuable structural biology information to interpret binding affinities, specificities, and diversity of K + channel‐nature toxin interactions. Proteins 2008. © 2007 Wiley‐Liss, Inc.