On the Role of the Solvent Environment in the Folding and Unfolding of Amphipathic Helices

The role of water in the formation of proteins is not well understood at the atomic level where these interactions occur in vivo. While folding necessarily results from the complex interplay between hydrophobic and hydrophilic groups in close proximity, the details how water contributes to this process, especially in the early stages of folding, remains unclear. Amphipathic helices have a defined secondary structure, whereby the peptide folds in such a way that the hydrophobic amino acid side chains are aligned on one side of the helix and the hydrophilic residues on the other. This type of helix has gained interest due to being a fold typically adopted by antimicrobial peptides (AMPs), which can penetrate a wide range of microbial membrane structures and have potential as a treatment for infectious diseases. Presently, it is unclear as to whether or not these secondary structures are formed in aqueous solution or require contact with a hydrophobic surface to nucleate their folding. Such information is key to understanding how AMPs might penetrate membrane structures, for which the precise mechanism has not been fully established. The present study explores the solvation of peptides with repeating residues of lysine and leucine (KLL), known to fold into amphipathic helices, in amphiphilic solutions. Using a combination of Molecular Dynamics simulations, Neutron Diffraction, Nuclear Magnetic Resonance spectroscopy, and Circular Dichroism, it has been possible to elucidate the interactions important for the folding of these peptides. By investigating these model peptides in amphiphilic solutions the folding state can be controlled and the details of these interactions revealed.