Structural and functional behavior of biologically active monomeric melittin

Melittin is a well-known water-soluble toxic peptide present in bee venom of Apis mellifera, capable of interacting with and disrupting cell membranes thus producing many effects on living cells. Additionally, melittin induces activation of phospholipases and calmodulin upon interaction with cellular membranes. The conformation and aggregation state adopted by melittin in solution depends on several factors including the peptide concentration, ionic strength, pH and the nature of the ions in the aqueous medium. Such conformational dependence on the peptide environment gives new insights over the currently available 3D structures of melittin and, ultimately, over its biologically functional unit. Based on crystallographic data, the melittin tetramer has been proposed as its bioactive form. Contrarily to such data, we show in this work the results obtained from molecular dynamics simulations, which clearly indicate that the tetrameric organization of melittin is not stable under biological conditions dissociating after 2.5 ns through a 10 ns trajectory. We found that the terrameric form of melittin is stable only in conditions of high pH and high peptide concentration in the molecular dynamics simulations. Moreover, when in plasma melittin appears to be a random coil monomer, folding only upon interaction with biological membranes. In summary, these findings elucidate several properties of melittin structure and dynamics, projecting significant implications in the study of its biological function. (c) 2006 Elsevier Inc. All rights reserved.