Conformational Transitions of Melittin between Aqueous and Lipid Phases: Comparison of Simulations with Experiments.

Peptides are promising drug candidates with advantageous therapeutic properties. However, their inherent flexibility makes the development of structure-activity relationships difficult. Molecular dynamics simulations have been widely used to study peptide conformations, but they are limited by force field parameters. We explore the ability of nine combinations of commonly used protein, lipid, and water force field models (ff99/tip3p, ff14SB/tip3p, c22/tip3p, c22/tips3p, c36/tip3p, c36/tips3p, c36m/tip3p, c36m/tips3p, and g53a6/spc) in capturing the conformational dynamics of the antimicrobial peptide melittin between the aqueous and model membrane environments. Circular dichroism experiments of melittin displayed a structural transition from a random coil in an aqueous solution to a helix in the presence of a model membrane. Of the protein/lipid/water models that we examined, c22 with the tips3p water model correctly recapitulated the experimentally observed disordered conformations in an aqueous solution and helical conformations in the presence of the model membrane, followed by c36/tips3p. Hydration analysis revealed that the tips3p water model leads to stronger peptide-water interactions, which, in turn, better describe the solvation and its effects on conformational distributions in aqueous and membrane environments. The results of this study reveal the secondary structure preferences of various force fields and emphasize the role of hydration and microenvironment in modulating peptide conformations.