Editorial [Hot Topic: The Multi-Purpose Amphiphilic α-Helix - A Historical Perspective (Guest Editors: David Phoenix and Frederick Harris)]

Proteins play a fundamental role in membrane dependent processes and due to the inherently amphiphilic nature of the bilayer, such proteins must accommodate both polar and non-polar environments. In response, membrane interactive proteins adopt amphiphilic secondary structures, which can be subdivided into several general classes but it is generally accepted that amphiphilic α-helices form the major example of these classes. Members of this latter structural type may possess primary amphiphilicity, which is exhibited by most transmembrane α-helices, or secondary amphiphilicity, which is generally associated with α-helices that are active at a lipid / membrane interface [1]. The secondary amphiphilicity of α-helices is characterised by an ordered spatial segregation of hydrophobic and hydrophilic amino acid residues about the α-helical long axis and, historically, was first reported within the molecules of myoglobin and haemoglobin during the mid 1960s [2]. The ubiquitous occurrence and clear functional importance of these α- helical structures was soon realized and, over the subsequent decades, led to a series of theoretical approaches designed to enable their identification from sequence information alone. These approaches were generally based on the fact that the secondary amphiphilicity of α-helices is reflected in the primary structure of a protein by the periodic occurrence of doublets or triplets of polar or apolar residues [3]. The earliest of the techniques used to identify this residue periodicity was developed in the late 1960s and were graphical with the major example being the α-helical wheels of Schiffer-Edmundson [4]. Over the next few decades, it became apparent that there was a need to formally quantify the amphiphilicity of protein a-helices, which led to the development of measures of amphiphilicity such as the Amphipathic Index (AI) of Cornette et al., [5] and the Molecular Hydrophobic Potential (MHP) of Brasseur [6]. Undoubtedly though, the most commonly used measure of amphiphilicty developed within this period was the Hydrophobic Moment (< μH >) of Eisenberg [7], which was developed not long after by this author to give Hydrophobic Moment Plot methodology [8]. This methodology attempted to broadly classify membrane interactive a-helices as either transmembrane or active at the interface (surface-active) and numerous authors have adapted the methodology to characterize the structure / function relationships of subclasses of these α-helices [1]. Probably the most used of these adapted methodologies is the taxonomy of Segrest et al. [9] which subclassifies membrane interactive amphiphilic α- helices as those of apolipoproteins (class A), lytic peptides (class L), hormones (class H) and transmembrane proteins (class M). The MHP of Brasseur [6] has been used as a basis to make similar subclassifications of amphiphilic a-helices [1] and most recently has been used to aid the identification of oblique orientated α-helices [10]. Since the first description of amphiphilic α-helices, they have formed the basis of numerous papers, reviews, conferences and books. A major contribution to the literature of these α-helices was made by publication of “The Amphipathic Helix” (ISBN: 0849349265) in 1993, which was edited by Richard Epand and provided a comprehensive overview of the major α- helical classes then known. This Hot Topics issue of CPPS provides an update on some of these α-helical classes and introduces a number of such classes that have been discovered since. Amphiphilic α-helical defence peptides were first reported in the late 1980s and are effectors of innate immunity that generally exert antimicrobial activity through permeabilising the membranes of target organisms. These peptides are attractive propositions for development as novel antimicrobial agents and, in this capacity, attempts to optimize their lytic activity and target specificity by the use of combinatorial synthesis and directed evolution are reviewed here by Mariana De Castro et al. Moreover, based on the lessons learnt from structure / function studies on these defence peptides, lipopeptides are currently being studied for development as potent agents against pathogenic fungi and yeast, reviewed here by Yechel Shai et al. Amphiphilic α-helical defence peptides have also been found to show potent anticancer activity and progress in the understanding of this activity is reviewed by Sarah Dennison et al. Functionally related to defence peptides are α-helical peptide venoms such as mastoparan (MP), which is known to bind and modulate G-proteins in addition to a variety of other intracellular targets. MP, along with its analogues and chimaera, has proved a crucial tool in probing diverse biological phenomenon, particularly G-protein function, and is reviewed here by Sarah Jones and John Howl. Another class of α-helical proteins that show the potential for biological application are antifreeze proteins (AFPs), some of which are able to stabilize membranes and thereby function as cryoprotectants. The development of AFPs in this capacity is hampered by the fact that it is currently not possible to predict whether a particular AFP will stabilize or destabilize a given lipid system. However, some progress in this direction has been made and is reviewed here by Steven Inglis et al. Around the same time as defence peptides were discovered, oblique orientated α-helices were first reported in viral proteins, promoting the fusion of host and viral membranes.......