Molecular Dynamics of the KcsA K + Channel in a Bilayer Membrane

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Molecular dynamics (MD) simulations of an atomic model of the KcsA K + channel embedded in an explicit dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayer solvated by a 150 mM KCl aqueous salt solution are performed and analyzed. The model includes the KcsA K + channel, based on the recent crystallographic structure of Doyle et al. (1998, Science. 280:69–77), 112 DPPC, K + and Cl − ions, as well as over 6500 water molecules for a total of more than 40,000 atoms. Three K + ions are explicitly included in the pore. Two are positioned in the selectivity filter on the extracellular side and one in the large water-filled cavity. Different starting configurations of the ions and water molecules in the selectivity filter are considered, and MD trajectories are generated for more than 4 ns. The conformation of KcsA is very stable in all of the trajectories, with a global backbone root mean square (RMS) deviation of less than 1.9 Å with respect to the crystallographic structure. The RMS atomic fluctuations of the residues surrounding the selectivity filter on the extracellular side of the channel are significantly lower than those on the intracellular side. The motion of the residues with aromatic side chains surrounding the selectivity filter (Trp 67, Trp 68, Tyr 78, and Tyr 82) is anisotropic with the smallest RMS fluctuations in the direction parallel to the membrane plane. A concerted dynamic transition of the three K + ions in the pore is observed, during which the K + ion located initially in the cavity moves into the narrow part of the selectivity filter, while the other two K + ions move toward the extracellular side. A single water molecule is stabilized between each pair of ions during the transition, suggesting that each K + cation translocating through the narrow pore is accompanied by exactly one water molecule, in accord with streaming potential measurements (Alcayaga et al., 1989, Biophys. J. 55:367–371). The displacement of the ions is coupled with the structural fluctuations of Val 76 and Gly 77, in the selectivity filter, as well as the side chains of Glu 71, Asp 80, and Arg 89, near the extracellular side. Thus the mechanical response of the channel structure at distances as large as 10–20 Å from the ions in the selectivity filter appears to play an important role in the concerted transition.