Conformational Dynamics and Energetics of Melittin and its Diastereomer Interacting with POPC and POPG Lipid Bilayers: A Molecular Dynamics Study

Abstract

Often amphipathic membrane-active peptides assume helical secondary structure when partitioning into lipid membranes. Characterizing this membrane-induced folding process at single molecule level is fundamental to understanding peptide lipid-membrane interactions. To this end, we use all-atom, long time scale (∼1µs) molecular dynamics (MD) simulations to investigate and compare the conformational dynamics and energetics of the well-studied peptide melittin (MWT) and one of its less-studied diastereomer, with four D-amino acids, (MD4) interacting respectively with a zwitterionic POPC and an anionic POPG lipid bilayer. Unlike in previous MD studies, we start from a completely folded conformation of the peptides and follow their unfolding through free MD simulations. We find that (i) both MWT and MD4 unfold in solution and remain mostly disordered; (ii) MWT binds to both POPC and POPG, remaining mostly folded (with more than 70% helical content); and (iii) MD4 binds only to POPG and it is mostly disordered (with less than 40% helical content). Furthermore, by calculating the potential of mean force, as a function of peptide-lipid bilayer separation, we have determined the relative dissociation energy of MWT and MD4 from POPG, which can be related to the membrane induced folding energy of melittin. To our knowledge, this is the first MD study of the MD4 melittin analog, and the obtained results are in good agreement with previous experimental studies. Work supported in part by a grant from the MU Research Board. The computation for this work was performed on the high HPC infrastructure provided by RCSS and in part by the NSF under grant number CNS-1429294 at the University of Missouri, Columbia MO.