Absorption and folding of melittin onto lipid bilayer membranes via unbiased atomic detail microsecond molecular dynamics simulation

Abstract

Unbiased molecular simulation is a powerful tool to study the atomic details driving functional structural changes or folding pathways of highly fluid systems, which present great challenges experimentally. Here we apply unbiased long-timescale molecular dynamics simulation to study the ab initio folding and partitioning of melittin, a template amphiphilic membrane active peptide. The simulations reveal that the peptide binds strongly to the lipid bilayer in an unstructured configuration. Interfacial folding results in a localized bilayer deformation. Akin to purely hydrophobic transmembrane segments the surface bound native helical conformer is highly resistant against thermal denaturation. Circular dichroism spectroscopy experiments confirm the strong binding and thermostability of the peptide. The study highlights the utility of molecular dynamics simulations for studying transient mechanisms in fluid lipid bilayer systems. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

Mechanisms of Integral Membrane Protein Insertion and Folding

“…During the time course of the simulation, the peptide is never seen to leave the membrane and return to the aqueous phase, which is the behavior expected from extensive studies of the interactions of melittin with bilayers (above). Indeed, microsecond-scale simulations of melittin folding at the membrane interface are in quantitative agreement with experiments [40, 41]. …”

Molecular simulations of venom peptide‐membrane interactions: Progress and challenges

“…Independent of resolution of the force field used, classical (i.e., unbiased) MD simulation are used to address questions including, but not limited to, the spontaneous binding of the peptide to the membrane surface, including conformational changes in the peptide, the penetration‐depth and orientation of the peptide at the water–lipid interface, the identification of peptide residues that control lipid binding, the effect of peptide binding on the local structure of the membrane, and the effect of lipid composition or mutations in the peptide on these properties. For pore‐forming peptides, classical MD simulations are also used to study the structure and stability of preformed pores or the first steps in pore formation …”

“…Specific questions include identifying the conformational changes in the peptide induced by membrane binding, the insertion depth and orientation as well as potential aggregation of the peptide at the water‐lipid interface. A series of recent studies on the spontaneous binding of the bee venom peptide melittin to neutral phospholipid bilayers have demonstrate the insight that can be gained from atomistic simulations but also clearly highlighted some of the challenges. Andersson et al reported a 17‐µs MD simulation of melittin binding to a DOPC membrane.…”

“…In contrast, a 2‐µs simulation with the OPLS force field failed to reproduce the per‐residue helicity. In a similar study, Chen et al carried out a set of unbiased, ∼2‐µs long MD simulations to study the folding of melittin on a POPC membrane including the effect of peptide binding on the local structure of the membrane. Simulations were started from a fully extended peptide.…”

Mechanisms of Membrane Pore Formation by Amyloidogenic Peptides in Amyotrophic Lateral Sclerosis

“…To overcome this problem we use an elevated temperature approach, which has been shown to increase sampling, membrane partitioning, and folding kinetics in lipid bilayers by several orders of magnitude without affecting the underlying thermodynamics. [13][14][15] To test the thermal response of D1, we performed circular dichroism (CD) measurements of D1 in phosphate buffer as well as in the presence of large unilamellar 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) vesicles. While the peptide does not appear to change its overall fold in solution at higher temperatures, the presence of vesicles results in an increase of secondary structure at higher temperatures.…”