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Biophys J, November 2000, p. 2322-2330, Vol. 79, No. 5
and
*Department of Biochemistry, The George S. Wise Faculty of Life
Sciences, Tel Aviv University, Ramat Aviv 69978, Israel, and
Beckman Institute for Advanced Science and Technology and
Department of Physics and Center for Biophysics and Computational
Biology, University of Illinois, Urbana, Illinois 61801 USA
Alamethicin is a hydrophobic antibiotic peptide 20 amino
acids in length. It is predominantly helical and partitions into lipid
bilayers mostly in transmembrane orientations. The rate of the peptide
transverse diffusion (flip-flop) in palmitoyl-oleyl-phosphatidylcholine vesicles has been measured recently and the results suggest that it
involves an energy barrier, presumably due to the free energy of
transfer of the peptide termini across the bilayer. We used continuum-solvent model calculations, the known x-ray crystal structure
of alamethicin and a simplified representation of the lipid bilayer as
a slab of low dielectric constant to calculate the flip-flop rate. We
assumed that the lipids adjust rapidly to each configuration of
alamethicin in the bilayer because their motions are significantly
faster than the average peptide flip-flop time. Thus, we considered the
process as a sequence of discrete peptide-membrane configurations,
representing critical steps in the diffusion, and estimated the
transmembrane flip-flop rate from the calculated free energy of the
system in each configuration. Our calculations indicate that the
simplest possible pathway, i.e., the rotation of the helix around the
bilayer midplane, involving the simultaneous burial of the two termini
in the membrane, is energetically unfavorable. The most plausible
alternative is a two-step process, comprised of a rotation of
alamethicin around its C-terminus residue from the initial
transmembrane orientation to a surface orientation, followed by a
rotation around the N-terminus residue from the surface to the final
reversed transmembrane orientation. This process involves the burial of
one terminus at a time and is much more likely than the rotation of the
helix around the bilayer midplane. Our calculations give flip-flop
rates of ~10
7/s for this
pathway, in accord with the measured value of 1.7 × 106/s.
Biophys J, November 2000, p. 2322-2330, Vol. 79, No. 5
© 2000 by the Biophysical Society 0006-3495/00/11/2322/09 $2.00
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