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Biophys J, January 2000, p. 55-69, Vol. 78, No. 1
and
*Laboratory of Molecular Biophysics, Department of Biochemistry,
University of Oxford, South Parks Road, Oxford OX1 3QU, England;
Cambridge Centre for Molecular Recognition, Department of
Biochemistry, University of Cambridge, Cambridge CB2 1GA, England; and
BIOSON Research Institute and Department of Biophysical
Chemistry, University of Groningen, 9747 AG Groningen, the Netherlands
The M2 protein of influenza A virus forms homotetrameric
helix bundles, which function as proton-selective channels. The native form of the protein is 97 residues long, although peptides representing the transmembrane section display ion channel activity, which (like the
native channel) is blocked by the antiviral drug amantadine. As a small
ion channel, M2 may provide useful insights into more complex channel
systems. Models of tetrameric bundles of helices containing either 18 or 22 residues have been simulated while embedded in a fully hydrated
1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidylcholine bilayer. Several different starting models have been used. These suggest that the simulation results, at least on a nanosecond time
scale, are sensitive to the exact starting structure. Electrostatics calculations carried out on a ring of four ionizable aspartate residues
at the N-terminal mouth of the channel suggest that at any one time,
only one will be in a charged state. Helix bundle models were mostly
stable over the duration of the simulation, and their helices remained
tilted relative to the bilayer normal. The M2 helix bundles form closed
channels that undergo breathing motions, alternating between a tetramer
and a dimer-of-dimers structure. Under these conditions either the
channel forms a pocket of trapped waters or it contains a column of
waters broken predominantly at the C-terminal mouth of the pore. These
waters exhibit restricted motion in the pore and are effectively
"frozen" in a way similar to those seen in previous simulations of
a proton channel formed by a four-helix bundle of a synthetic
leucine-serine peptide (Randa et al., 1999, Biophys. J.
77:2400-2410).
Biophys J, January 2000, p. 55-69, Vol. 78, No. 1
© 2000 by the Biophysical Society 0006-3495/00/01/55/15 $2.00
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