Modeling KCNQ1 Channel and KCNE1 Interactions

Abstract

KCNQ1 is the pore-forming component of the slow delayed rectifier (Iks) channel in human heart. Although KCNQ1 can function as a voltage-gated (Kv) channel on its own, it requires KCNE1 to modulate its functions. To understand the mechanism of how KCNE1 modulate KCNQ1, molecular simulations are employed to model the interactions between KCNQ1 and KCNE1. A homology model of KCNQ1 was constructed based on the crystal structure of Kv1.2-Kv2.1 paddle chimera channel (PDB entry: 2R9R) template. For KCNE1, we used a NMR structure as an initial conformation, and manually adjusted the orientations of its N- and C- terminal domains to avoid their folding into membrane. Then 100ns molecular dynamics (MD) simulations were conducted to sample possible conformations of KCNE1 in POPC lipid bilayers. The cluster analysis was conducted on KCNE1 tansmembrane domain (KCNE1-TMD) from 40ns to 100ns simulation period. Five representative structures of KCNE1-TMD were selected, and used for docking simulations to KCNQ1. We performed 2 dimensional Brownian Dynamics (2D-BD) protein-docking simulations on each representative structure of KCNE1-TMD and KCNQ1 homology model. After selecting compact complexes by using a distance-based filter to remove loose contact complexes, a series of experimental restraints were applied to select one final KCNQ1/KCNE1-TMD complex structure. The N- and C- terminal domains of KCNE1 were reconstructed to generate the whole complex of KCNQ1/KCNE1, and followed by 100ns MD simulations in explicit membrane environment. For comparison, we also conducted 100ns MD simulations on KCNQ1 alone. Based on the two simulation studies, we analyzed the dynamics of the KCNQ1 channel with and without KCNE1 present through a systematic examination of hydrogen bond network patterns and ion permeation pathway of the channel. The results could provide us helpful insights of the molecular mechanism of how KCNE1 modulating KCNQ1 channel.