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Biophys J, February 2002, p. 772-780, Vol. 82, No. 2
and
*Department of Biochemistry, Weill Medical College of Cornell
University, New York, New York 10021 USA; and
Membrane Transport Research Group (GRTM), Department of
Physics, Université de Montréal, Montréal H3C 3J7,
Canada
The side chain of Glu-71 of the KcsA K+
channel, an important residue in the vicinity of the selectivity
filter, was not resolved in the crystallographic structure of Doyle et
al. (Doyle, D. A., J. M. Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis, S. L. Cohen, B. T. Chait, and R. MacKinnon. 1998. Science. 280:69-77). Its atomic
coordinates are undetermined and its ionization state is unknown. For
meaningful theoretical and computational studies of the KcsA
K+ channel, it is essential to address questions about the
conformation and the ionization state of this residue in detail. In
previous MD simulations in which the side chain of Glu-71 is protonated and forming a strong hydrogen bond with Asp-80 it was observed that the
channel did not deviate significantly from the crystallographic structure (Bernèche, S., and B. Roux. 2000. Biophys.
J. 78:2900-2917). In contrast, we show here that the structure of
the selectivity filter of the KcsA channel is significantly disrupted
when these side chains are fully ionized on each of the four monomers.
To further resolve questions about the ionization state of Glu-71 we
calculated the pKa value of this residue using molecular
dynamics free energy simulations (MD/FES) with a fully flexible system including explicit solvent and membrane and finite-difference Poisson-Boltzmann (PB) continuum electrostatics. It is found that the
pKa of Glu-71 is shifted by ~+10 pKa units.
These results strongly suggest that Glu-71 is protonated under normal conditions.
Biophys J, February 2002, p. 772-780, Vol. 82, No. 2
© 2002 by the Biophysical Society 0006-3495/02/02/772/09 $2.00
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