Molecular dynamics simulations of bovine lactoferricin: turning a helix into a sheet

Abstract

Bovine lactoferricin is a 25-residue peptide that is excised through pepsin cleavage in the stomach from the intact 80 kDa bovine milk protein lactoferrin. This basic peptide contains a single disulfide crosslink and is considerably more active as an antimicrobial peptide than the intact protein. It has been suggested that the dramatic difference in potency is related to a change in the secondary and tertiary structure of this peptide, moving from a mixed α-helical β-strand region in the protein to an amphipathic twisted antiparallel β-sheet in the peptide. Here we have used equilibrium and restrained molecular dynamics calculations to compare the stability of the solution structure of the isolated peptide with that excised from the intact protein. Simulations were performed for fully solvated peptides in the absence and presence of 250 mM salt. Our results show that the peptide as released from the protein is relatively unstable, particularly in the absence of salt. However, even though the simulations extended over 60 nsecs, no interconversion could be observed between the crystal and solution structures, unless a relatively small directional force was exerted on the peptide. A pathway for the structural transition from a helical to a sheet structure was identified in this fashion.