Permethylation alters the conformational transitions and the complexing ability of melittin: a model for methylated proteins.

Melittin exhibits a transition from random-coil monomer to helical tetramer as a function of peptide concentration [J. Bello, H. R. Bello, and E. Granados (1982) Biochemistry, Vol. 21, pp. 461-465]. When permethylated on each of the four amino groups (Gly-1 N alpha and Lys-7, 21, and 23 N epsilon) to yield trimethylammonium groups, melittin exists as a random coil and does not show any concentration-dependent conformational transition (up to 290 microM). Acylation of the amino groups of melittin with glycine or 5-aminopentanoic acid followed by permethylation increases helix formation, but to a lesser extent than for the unmethylated aminoacylmelittin derivatives. The results are discussed in relation to hydrophobicity, charge repulsions, and ion binding. Melittin, and more weakly, permethylated melittin (MLT-Me) form helical hybrids with an anionic random-coil melittin analogue (E-MLT), in which all the lysine and arginine residues of melittin were replaced by glutamate residues. The hybrid between MLT-Me and E-MLT shows a concentration-dependent increase in helicity. E-MLT, when succinylated at the N-terminal glycine (E-MLT-suc), forms a stronger hybrid with MLT-Me, possibly as a result of increased electrostatic interaction between equal but opposite charges in E-MLT-suc (net charge -6) and MLT-Me (net charge +6). The hybrids exhibit both cold- and heat-induced denaturation, similar to the phenomenon exhibited by proteins. The hybrids also exhibit significant residual structures in the temperature range of 80-100 degrees C, which may be similar to the molten globular states that have been suggested for proteins.