HELIX BENDING IN ALAMETHICIN - MOLECULAR-DYNAMICS SIMULATIONS AND AMIDE HYDROGEN-EXCHANGE IN METHANOL

Molecular dynamics simulations of alamethicin in methanol were carried out with either a regular alpha-helical conformation or the x-ray cry stal structure as starting structures, The structures rapidly converge d to a well-defined hydrogen-bonding pattern with mixed alpha-helical and 3(10)-helical hydrogen bonds, consistent with NMR structural chara cterization, and did not unfold throughout the 1-ns simulation, despit e some sizable backbone fluctuations involving reversible breaking of helical hydrogen bonds, Bending of the helical structure around residu es Aib10-Aib13 was associated with reversible flips of the peptide bon ds involving G11 (Aib10-G11 or G11-L12 peptide bonds), yielding discre te structural states in which the Aib10 carbonyl or (rarely) the G11 c arbonyl was oriented away from the peptide helix, These peptide bond r eversals could be accommodated without greatly perturbing the adjacent helical structure, and intramolecular hydrogen bonding was generally maintained in bent states through the formation of new (non-alpha or 3 (10)) hydrogen bonds with good geometries: G11 NH-VS CO (inverse gamma turn), Aib13 NH-Aib8 CO (pi-helix) and, rarely, L12 NH- QT NH (pi-hel ix). These observations may reconcile potentially conflicting NMR stru ctural information for alamethicin in methanol, in which evidence for conformational flexibility in the peptide sequence before P14 (G11-Aib 13) contrasts with the stability of backbone amide NH groups to exchan ge with solvent, Similar reversible reorientation of the Thr11-Gly12 p eptide bond of melittin is also observed in dynamics simulations in me thanol (R. B. Sessions, N. Gibbs, and C. E, Dempsey, submitted). This phenomenon may have some role in the orientation of the peptide carbon yl in solvating the channel lumen in membrane ion channel stales of th ese peptides.