The protonation state of the Glu-71/Asp-80 residues in the KcsA potassium channel: A first-principles QM/MM molecular dynamics study

Although a few x-ray structures of the KcsA K 1 channel have been crystallized several issues concerning the mechanisms of the ionic permeation and the protonation state of the selectivity. filter ionizable side chains are still open. Using a first- principles quantum mechanical/molecular mechanical simulation approach, we have investigated the protonation state of Glu-71 and Asp-80, two important residues located in the vicinity of the selectivity filter. Results from the dynamics show that a proton is shared between the two residues, with a slight preference for Glu-71. The proton is found to exchange on the picosecond timescale, an interesting phenomenon that cannot be observed in classical molecular dynamics. Simulations of different ionic loading states of the filter show that the probability for the proton transfer is correlated with the filter occupancy. In addition, the Glu-71/Asp- 80 pair is able to modulate the potential energy pro. le experienced by a K 1 ion as it translates along the pore axis. These theoretical predictions, along with recent experimental results, suggest that changes of the filter structure could be associated with a shift in the Glu-Asp protonation state, which in turn would influence the ion translocation.