Atomistic Simulations of Ion Channels - Computational Neuroscience: A Comprehensive Approach - page 51

Figure 2.5
Current-voltage curves for alamethicin K18 as function of pH. Many independent
measurements have been superimposed. The green data indicate that K18 is cation
selective at high pH (positive reversal potential, where the current equals 0), red is
not selective (intermediate pH), whereas yellow and blue are anion selective (low
pH). See [20] for more details. Figure provided by Dr. Woolley. (See color insert.)
tempt to link the models with experimental conductance data. The simulations are of
duration comparable to the mean passage time of a single ion through such a channel
(ca. 5 ns is equivalent to an ionic conductance of 250 pS at 125 mV). Although these
simulations have suggested strongly which experimental conductance levels corre-
spond to which aggregation number of helices, a more reliable method to connect an
atomistic model to conductance levels is highly desirable. Because of its simplicity,
alamethicin has also been a useful test system to investigate the effect of different
simulation algorithms [114], and for one particular system (N6, a parallel hexameric
bundle) a simulation has been extended to 100 ns [109], one the longest simulations
on a channel to date. In this fashion we obtained a validated 'best guess' model for
at least one conductance level of the Alm channel, which should prove useful as the
basis for future more in depth calculations of channel electrostatics and permeation
models.
Woolley and coworkers designed an interesting variant of alamethicin, called K18
[105]. In this peptide, the glutamate/glutamine in position 18 has been replaced by
a lysine that points into the pore, and two alamethicin peptides have been covalently
coupled. The resulting peptide shows preferential stabilization of half the channel
levels of normal alamethicin, suggesting pairs of helices insert simultaneously and
contribute to the channels. This makes it easier to determine the number of helices
in a given measured conductance level. A second interesting property of K18 is that
it forms channels with a pH dependent selectivity [20].