Packing interactions of aib‐containing helices: Molecular modeling of parallel dimers of simple hydrophobic helices and of alamethicin

Abstract

alpha-Aminoisobutyric acid (Aib) is a helicogenic alpha, alpha-dimethyl 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 ensembles of approximately parallel helix dimers. Analysis of variations in geometrical and energetic parameters within ensembles defines how tightly a pair of helices interact. Simple hydrophobic helix dimers are compared: Ala20, Leu20, Aib20, and P20, the latter a simple channel-forming peptide [G. Menestrina, K.P. Voges, G. Jung, and G. Boheim (1986) Journal of Membrane Biology, Vol. 93, pp. 111-132]. Ala20 and Leu20 dimers exhibit well-defined ridges-in-grooves packing with helix crossing angles (omega) of the order of +20 degrees. Aib20 alpha-helix dimers are much more loosely packed, as evidenced by a wide range of omega values and small helix-helix interaction energies. However, when in a 3(10) conformation Aib20 helices pack in three well-defined parallel modes, with omega ca. -15 degrees, +5 degrees, and 10 degrees. Comparison of helix-helix interaction energies suggests that dimerization may favor the 3(10) conformation. P20, with 8 Aib residues, 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 of alamethicin, and of an alamethicin derivative in which all Aib residues are replaced by Leu. This substitution has little effect on helix-helix packing. Rather, such interactions appear to be sensitive to interactions 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, interactions between polar side chains may be more critical.

Molecular dynamics of individual alpha-helices of bacteriorhodopsin in dimyristol phosphatidylocholine. I. Structure and dynamics

“…This is related to speculation about the possible functional roles of proline residues in membrane proteins (Deber et al, 1990a,b;Wil-liams and Deber, 1991;Heijne, 1991). It is also similar to 1 2 3 4 5 6 7 8 9 10 11 2llA l 1 2 3 4 5 6 7 8 9 10 11 12 results for isolated a-helices in vacuum that suggested greater motional change about a hinge-axis (Sankararamakrishnan et al, 1991; Sankararamakrishnan and Vishveshwara, 1990Sansom, 1992;Breed et al, 1995;Sankararamakrishnan and Sansom, 1994) and to simulation results for single proline containing a-helices in explicit water (Yun et al, 1991). The result further suggests that the proline residues can be thought of as local helical hinge-points allowing two separate relatively rigid bodies to be functionally separated.…”

“…An extensive series of simulations have been performed on proline containing a-helices in vacuum (Sankararamakrishnan et al, 1991;Sankararamakrishnan and Visveshwara, 1990Sansom, 1992;Breed et al, 1995;Sankararamakrishnan and Sansom, 1994). One of the central goals of the vacuum simulations was to compare the helices with prolines against those that did not contain proline.…”

Structure and Function of Membrane-Lytic Peptides

“…Various models for the molecular mechanism of alamethicin voltage-gating are based on interactions of the alamethicin helix dipole with the electric field (reviewed in Woolley and Wallace, 1992;Cafiso, 1994;Breed et al, 1995;Bechinger, 1997). Voltage gating involves one or several reorientations of the helix dipole, enhanced partitioning of alamethicin from solution into the membrane (Stankowski et al, 1988), and membrane insertion of the N-terminus (Okazaki et al, 2003).…”

The pore domain of the nicotinic acetylcholine receptor: molecular modeling, pore dimensions, and electrostatics

“…Our implementation of simulated annealing via restrained molecular dynamics (SA/MD) has already been described in detail (Kerr and Sansom, 1993;Kerr et al, 1994;Breed et al, 1995;Sankararamakrishnan and Sansom, 1995ab;Sansom and Kerr, 1995;Sansom et al, 1995a,b), and so only a brief account is provided here. Furthermore, as the modeling of the closed state of the nAChR pore has already been described (Sansom et al, 1995a), the following description applies specifically to modeling the open state.…”