Molecular basis of inhibitory peptide maurotoxin recognizing Kv1.2 channel explored by ZDOCK and molecular dynamic simulations

Abstract

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 beta-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.

Structural Basis for Toxin Resistance of β4-Associated Calcium-activated Potassium (BK) Channels

“…1C). To understand this discrepancy, a computational technique was used to determine the structural conformation of the mSlo turret (15,16). For the unbound mSlo channel, the starting structure of mSlo was found to be very unstable during the 5-ns molecular dynamic simulations (MDs).…”

“…The following procedures of clustering and screening of reasonable ChTX-mSlo complex structures were similar to our previous work (15,16).…”

“…Based on this, we constructed the closed mSlo structure using three steps. (i) The mSlo turret conformation was obtained through a segment-assembly homology modeling method (15,16). (ii) The rest of the mSlo structure was directly modeled using the KcsA structure (Protein Data Bank code 1BL8) as a template through the SWISSMODEL server.…”

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

“…Several theoretical docking studies have suggested that this lysine residue protrudes into the channel selectivity filter (Yi et al, 2008;Chen et al, 2011;Chen and Chung, 2012), but in this case K16, K17, and R9 were the most active residues, followed by K30, K25, K32, and K4, in forming hydrogen bonds with E355, E353, and D379, and D363 in the turret and pore helix region, respectively (Supplemental Table 1). A hydrogen bond is considered formed if the donor and acceptor atoms (nitrogen or oxygen) are within 3.2 Å of each other.…”

Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease

“…This program was employed for identifying the most reasonable candidate complexes. The detailed method of calculating binding free energies between inhibitory peptides and potassium channels was previously described (29,30).…”