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Molecular Dynamics Simulation of Transmembrane Polypeptide Orientational Fluctuations

David J. Goodyear ^*, Simon Sharpe , Chris W. M. Grant  and Michael R. Morrow ^*

^* Department of Physics and Physical Oceanography, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X7, Canada; and Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada

Correspondence: Address reprint requests to Michael R. Morrow, Fax: 709-737-8739; E-mail:myke{at}physics.mun.ca.

The orientation and motion of a model lysine-terminated transmembrane polypeptide were investigated by molecular dynamics simulation. Recent ²H NMR studies of synthetic polypeptides with deuterated alanine side chains suggest that such transmembrane polypeptides undergo fast, axially symmetric reorientation about the bilayer normal but have a preferred average azimuthal orientation about the helix axis. In this work, interactions that might contribute to this behavior were investigated in a simulated system consisting of 64 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and one -helical polypeptide with the sequence acetyl-KK-(LA)₁₁-KK-amide. In one simulation, initiated with the peptide oriented along the bilayer normal, the system was allowed to evolve for 8.5 ns at 1 atm of pressure and a temperature of 55°C. A second simulation was initiated with the peptide orientation chosen to match a set of experimentally observed alanine methyl deuteron quadrupole splittings and allowed to proceed for 10 ns. Simulated alanine methyl group orientations were found to be inequivalent, a result that is consistent with ²H NMR observations of specifically labeled polypeptides in POPC bilayers. Helix tilt varied substantially over the durations of both simulations. In the first simulation, the peptide tended toward an orientation about the helix axis similar to that suggested by experiment. In the second simulation, orientation about the helix axis tended to return to this value after an excursion. These results provide some insight into how interactions at the bilayer surface can constrain reorientation about the helix axis while accommodating large changes in helix tilt.

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