Alamethicin Helices in a Bilayer and in Solution: Molecular Dynamics Simulations

• Published in: Biophysical journal Vol. 76; no. 1; pp. 40 - 49
• Main Authors: Tieleman, D. Peter, Sansom, Mark S.P., Berendsen, Herman J.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 1999; Biophysical Society
• Subjects: Alamethicin - chemistry; Amino Acid Sequence; Biophysical Phenomena; Biophysics; Computer Simulation; Lipid Bilayers - chemistry; Models, Molecular; Molecular Sequence Data; Phosphatidylcholines - chemistry; Protein Conformation; Protein Structure, Secondary; Solutions; Thermodynamics
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(99)77176-6

Alamethicin is an α-helical channel-forming peptide, which inserts into lipid bilayers in a voltage-dependent, asymmetrical fashion. Nanosecond molecular dynamics simulations have been used to compare alamethicin conformation and dynamics in three different environments: 1) in water; 2) in methanol; and 3) inserted into a lipid (palmitoyl-oleoyl-phosphatidylcholine) bilayer to form a transmembrane helix. In the bilayer and in methanol, there was little change (C α RMSD ≈ 0.2 nm over 2 ns and 1 ns) from the initial helical conformation of the peptide. In water there were substantial changes (C α RMSD ≈ 0.4 nm over 1 ns), especially in the C-terminal segment of the peptide, which lost its α-helical conformation. In the bilayer and in methanol, the alamethicin molecule underwent hinge-bending motion about its central Gly-X-X-Pro sequence motif. Analysis of H-bonding interactions revealed that the polar C-terminal side chains of alamethicin provided an “anchor” to the bilayer/water interface via formation of multiple H-bonds that persisted throughout the simulation. This explains why the preferred mode of helix insertion into the bilayer is N-terminal, which is believed to underlie the asymmetry of voltage activation of alamethicin channels.