Structure and Dynamics of K Channel Pore-Lining Helices: A Comparative Simulation Study

• Published in: Biophysical journal Vol. 78; no. 1; pp. 79 - 92
• Main Authors: Shrivastava, Indira H., Capener, Charlotte E., Forrest, Lucy R., Sansom, Mark S.P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2000; Biophysical Society
• Subjects: Amino Acid Sequence; Animals; Bacterial Proteins - chemistry; Computer Simulation; Drosophila melanogaster; Drosophila Proteins; Humans; Hydrogen Bonding; Kinetics; Lipid Bilayers - chemistry; Models, Molecular; Molecular biology; Molecular Sequence Data; Phosphatidylcholines; Physics; Potassium Channels - chemistry; Potassium Channels, Inwardly Rectifying; Protein Structure, Secondary; Shaker Superfamily of Potassium Channels; Streptomyces
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(00)76574-X

Isolated pore-lining helices derived from three types of K-channel have been analyzed in terms of their structural and dynamic features in nanosecond molecular dynamics (MD) simulations while spanning a lipid bilayer. The helices were 1) M1 and M2 from the bacterial channel KcsA ( Streptomyces lividans), 2) S5 and S6 from the voltage-gated (Kv) channel Shaker ( Drosophila melanogaster), and 3) M1 and M2 from the inward rectifier channel Kir6.2 (human). In the case of the Kv and Kir channels, for which x-ray structures are not known, both short and long models of each helix were considered. Each helix was incorporated into a lipid bilayer containing 127 palmitoyloleoylphosphatidylcholine molecules, which was solvated with ∼4000 water molecules, yielding ∼20,000 atoms in each system. Nanosecond MD simulations were used to aid the definition of optimal lengths for the helix models from Kv and Kir. Thus the study corresponds to a total simulation time of 10 ns. The inner pore-lining helices (M2 in KcsA and Kir, S6 in Shaker) appear to be slightly more flexible than the outer pore-lining helices. In particular, the Pro-Val-Pro motif of S6 results in flexibility about a molecular hinge, as was suggested by previous in vacuo simulations (Kerr et al., 1996, Biopolymers. 39:503–515). Such flexibility may be related to gating in the corresponding intact channel protein molecules. Analysis of H-bonds revealed interactions with both water and lipid molecules in the water/bilayer interfacial region. Such H-bonding interactions may lock the helices in place in the bilayer during the folding of the channel protein (as is implicit in the two-stage model of membrane protein folding). Aromatic residues at the extremities of the helices underwent complex motions on both short (<10 ps) and long (>100 ps) time scales.