Sorting of Lipidated Peptides in Fluid Bilayers: A Molecular-Level Investigation

Nearest-neighbor recognition (NNR) measurements have been made for two lipidated forms of GlyCys, interacting with analogues of cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in the liquid-ordered (l(o)) and liquid-disordered (l(d)) phases. Interaction free energies that have been determined from these measurements have been used in Monte Carlo simulations to quantify the distribution of the peptides between liquid-ordered and liquid-disordered regions. These simulations have shown that significant differences in the lipid chains have a very weak influence on the partitioning of the peptide between these two phases. They have also revealed an insensitivity of the peptide partition coefficient, K-p, to the size of the l(o) and l(d) domains that are present. In a broader context, these findings strongly suggest that the sorting of peripheral proteins in cellular membranes via differential lipidation may be more subtle than previously thought.