The Amphipathic a Helix

The amphipathic a helix, defined as an a helix with opposing polar and nonpolar faces oriented along its long axis, is a common secondary structural motif in biologically active peptides and proteins. The discovery of this structural motif was made by studying space-filling models of 

There are now a wide range of methods available to detect domains with amphipathic helicial characteristics at the residue level. However, new methods for describing the amphipathic nature of protein segments at the atomic level are still under development. Attempts to incorporate atomic hydrophobicity values (Cornette et ai, 1987 Tanford, 1978) in describing the amphipathic nature of peptides or other molecules have been described (Eisenberg and McLachlan, 1986). In the future, however, side-chain flexibility, effective solvent-accessible surfaces, electrostatics, and molecular dynamics will have to be included to obtain an accurate description of the amphipathic nature of these protein fragments at an atomic level. 

In order to develop a comparison database with which to analyze the amphipathic helices of the apolipoproteins, we used COMBO, COMNET, and CONSENSUS to analyze five of the seven originally described classes of amphipathic helices (Fig. 4). Classes A, L, and H are included because these three represent surface-active amphipathic helices with measurable lipid affinity. 

Furthermore, as will be described later, a direct comparison of the properties of these two groups with those of class A has enabled us to hypothesize and identify many hitherto unknown properties of apolipoproteins and other class A amphipathic helical peptide analogs. Class M is included because it has significant lipid affinity (although it is not surface active), and class G is included because it is similar to certain types of nonclass A amphipathic helices also found in apolipoproteins. 

Positive Residues Residues tom Center Negative Residues 

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This discussion puts us in a position to define a set of structural and evolutionary objects the tracing of whose history via homology, as implied by sequence similarity, is the primary aim of sequence analyses. The simple view of protein folding produces a small set of structural components to consider. This is the set of regular secondary structures the amphipathic a helix, the transmembrane or hydrophobic a. helix, the... 

THE AMPHIPATHIC a HELIX A MULTIFUNCTIONAL STRUCTURAL MOTIF IN PLASMA APOLIPOPROTEINS... 

In parallel to LXR agonists, apoA-I mimetic peptides also promote RCT. Specifically, they have been reported to facilitate cholesterol efflux from macrophages and decrease atherosclerosis in apoE null mice fed a Western diet [13, 16, 222-224], ApoA-I mimetics are small synthetic peptides that mimic the amphipathic a-helix of apoA-I and thus its functionality [225], Several apoA-I mimetic peptides are currently under preclinical trials and clinical development (namely, D-4F, L-4F, 5F, 6F, 7F, 5A, ATI-5261, and ETC642). The apoA-I mimetic peptides, D-4F and L-4F, showed great promise in early human trials [226] leading to a phase I/II study in humans with high-risk CVD [227],... 

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