Conformational analysis of the 20-residue membrane-bound portion of melittin by conformational space annealing

The conformational space of the 20-residue membrane-bound portion of melittin has been investigated extensively with the conformational space annealing (CSA) method and the ECEPP/3 (Empirical Conformational Energy Program for Peptides) algorithm. Starting from random conformations, the CSA method finds that there are at least five different classes of conformations, within 4 kcal/mol, which have distinct backbone structures. We find that the lowest energy conformation of this peptide from previous investigations is not the global minimum-energy conformation (GMEC); but it belongs to the second lowest energy class of the five classes found here. In four independent runs, one conformation is found repeatedly as the lowest energy conformation of the peptide (two of the four lowest energy conformations are identical; the other two have essentially identical backbone conformations but slightly different side-chain conformations). We propose this conformation, whose energy is lower than that found previously by 1.9 kcal/mol, as the GMEC of the ECEPP/3 force field. The structure of the proposed GMEC is less helical and more compact than the previous one. It appears that the CSA method can find several classes of conformations of a 20-residue peptide starting from random conformations utilizing only its amino acid sequence information. The proposed GMEC has also been found with a modified electrostatically driven Monte Carlo method [D. R. Ripoll, A. Liwo, and H. A. Scheraga (1998) "New Developments of the Electrostatically Driven Monte Carlo Method: Test on the Membrane-Bound Portion of Melittin," Biopolymers, Vol. 46, pp. 117-126].