PACKING INTERACTIONS OF AIB-CONTAINING HELICES - MOLECULAR MODELING OF PARALLEL DIMERS OF SIMPLE HYDROPHOBIC HELICES AND OF ALAMETHICIN

alpha-Aminoisobutyric acid (Aib) is a helicogenic alpha, alpha-dimethy l amino acid found in channel-forming peptaibols such as alamethicin. Possible effects of Aib on helix-helix packing are analyzed. Simulated annealing via restrained molecular dynamics is used to generate ensem bles of approximately parallel helix dimers. Analysis of variations in geometrical and energetic parameters within ensembles defines how tig htly a pair of helices interact. Simple hydrophobic helix dimers are c ompared: Ala(20), Leu(20), Aib(20), and P20, the latter a simple chann el-forming peptide [ G. Menestrina, K. P. Voges, G. Jung, and G. Bohei m (1986) Journal of Membrane Biology, Vol. 93, pp. 111-132]. Ala(20), and Leu(20) dimers exhibit well-defined ridges-in-grooves packing with helix crossing angles (Omega) of the order of + 20 degrees. Aib(20) a lpha-helix dimers are much move loosely packed, as evidenced by a wide range of Omega values and small helix-helix interaction energies. How ever, when in a 3(10) conformation Aib(20), helices pack in three well -defined parallel modes, with Omega ca. -15 degrees, + 5 degrees and 1 0 degrees. Comparison of helix-helix interaction energies suggests tha t dimerization may favor the 3(10) conformation. P20, with 8 Aib resid ues, also shows looser packing of alpha-helices. The results of these studies of hydrophobic helix dimers are analyzed in the context of the ridges-in-grooves packing model. Simulations are extended to dimers o f alamethicin, and of an alamethicin derivative in which all Aib resid ues are replaced by Leu. This substitution has little effect on helix- helix packing. Rather, such interactions appear to be sensitive to int eractions between polar side chains. Overall, the results suggest that Aib may modulate the packing of simple hydrophobic helices, in favor of looser interactions. For more complex amphipathic helices, interact ions between polar side chains may be move critical. (C) 1995 John Wil ey & Sons, Inc.