Antimicrobial Peptides DOI: 10.1002/anie.201103589 The Generation of Antimicrobial Peptide Activity: A Trade-off between Charge and Aggregation?** Marc Torrent, Javier Valle, M.Victòria NoguØs, Ester Boix, and David Andreu* Antimicrobial peptides (AMPs) are innate immune system effectors with a vital role in the prevention of infection. Despite being actively researched in recent years for their potential therapeutic application against infectious diseases, [1] the molecular mechanisms by which AMPs exert their activity are not fully understood, although they clearly involve membrane binding and destabilization as a common essential step. [2] It is also well known that amphipathic structures, such as those of the typical AMPs magainin and cecropin, are favored for membrane binding and pore formation. [3] Interestingly, AMPs such as bacteriocins [4] and tempo- rins, [5] or proteins like lysozyme, [6] lactoferrin, [7] and eosino- phil cationic protein, [8] have recently been described to form amyloid-like structures. In addition, many amyloid proteins share with AMPs membrane-perturbing abilities such as binding to negatively charged membranes [9] or preference for liquid disordered domains. [10] For instance, amyloid-forming proteins, such as prion protein and amyloid-b protein, can destabilize phospholipid bilayers [11] and have even been described to possess some antimicrobial activity. [12] It has indeed been suggested that dementia and amyloid deposits that induce brain-barrier permeabilization and atrophy might result from lipopolysaccharide or other debris left over from previous bacterial infection. [13] All this evidence could be used to hypothesize that amyloid propensity and antimicrobial activity are related in the sense that aggregation-prone regions may have served as templates from which AMPs were evolutionarily derived. To identify structural features common to both amyloid and antimicrobial regions, we analyzed the amino acid frequency in amyloid-prone regions [14] and AMPs. Our inspection revealed that, for 80% of amino acid residues, there is a coincident tendency to be present in (or absent from) both antimicrobial and amyloid-like regions (Fig- ure 1 a). The good correlation between both tendencies suggests that they may be somehow related. Even more, the residue-intrinsic propensities for both properties, that is, the probability for an individual residue to be located in either aggregation-prone [15] or antimicrobial domains, [16] are also well correlated (Figure 1b). The main exceptions to this concurrent behavior were positively charged residues, favored in antimicrobial but detrimental in aggregation- prone regions. Figure 1. Aggregation and antimicrobial relationships. a) Frequency and b) aggregation versus antimicrobial propensity are plotted for amino acid residues in amyloid-prone regions and AMPs. Well- correlated and outlying residues are shown as squares and inverted triangles, respectively. Amino acid frequencies in amyloid-prone regions were obtained from Ref. [14], and in AMPs as detailed in the Supporting Information. Aggregation propensity values are from Ref. [15] and antimicrobial index from Ref. [16]. p values are in all cases < 0.01. [*] Dr. M. Torrent, J. Valle, Prof. D. Andreu Department of Experimental and Health Sciences Universitat Pompeu Fabra Dr. Aiguader 88, 08003 Barcelona (Spain) E-mail: david.andreu@upf.edu Prof. M. V. NoguØs, Dr. E. Boix Department of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, Biosciences Faculty Building C, 08193 Barcelona (Spain) [**] M.T. is the recipient of a postdoctoral grant from Alianza Cuatro Universidades (Spain). This work was supported by the European Union (HEALTH-F3-2008-223414), the Spanish Ministry of Science and Innovation (BIO2008-04487-CO3-02, BFU2009-09371), and the Generalitat de Catalunya (SGR2009-494, SGR2009-795). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201103589. 1 Angew. Chem. Int. Ed. 2011, 50,1–5  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Ü Ü