(482i) Mechanism of Protegrin Dimerization On Lipid Bilayer Membranes: Molecular Dynamics Simulation | AIChE

(482i) Mechanism of Protegrin Dimerization On Lipid Bilayer Membranes: Molecular Dynamics Simulation


Vivcharuk, V. - Presenter, University of Minnesota

The mechanism of antimicrobial activity of the 18-residue cationic peptide protegrin-1 (PG1) is investigated with atomic-scale molecular dynamics (MD) simulations. In particular, we study the oligomerization of protegrin molecules, because their activity is inseparable from oligomer peptide structures on the membranes of bacteria [1-3]. PG1 is known to form octameric pores in bacterial membranes that lyse the cell by preferentially allowing potassium diffusion [2].

One important question in elucidating the mechanism of antimicrobial activity is whether PG1 forms dimers and then oligomers in water, on the membrane surface, or deep in the membrane core. Literature studies propose different mechanisms and with the simulations we provide some clarity.

MD simulations measuring the free energy difference or the potential of mean force (PMF) between two protegrins under physiological conditions are used to elucidate the efficacy of such interaction in water buffers and in bilayer membranes. The simulated lipid membranes are composed of palmitoylphosphatidylethanolamine (POPE) and palmitoyloleoylphosphatidylglycerol (POPG) lipids, mimicking the bacterial membrane.

More than sixty separate 4 ns-long MD simulations with different orientations of PG1 dimers with anti-parallel and parallel orientations were carried out in different environments. To calculate the PMF we employed a combination of the constrained MD technique and the thermodynamic integration method. The application of the blocking method [4] indicates that our MD trajectories became uncorrelated after ~ 0.8 ns. We calculate the forces on the peptides due to the solvent and quantify the contribution of the effect due to the displacement of ions and water on the binding affinity. Ion contributions are shown to important at all length scales while solvent effects play an important role only in the contact region. The PMF can be used to predict measurable (but currently unknown) binding coefficients. In the presentation, we will reconstruct the minimum free energy path for the peptides to dimerize, oligomerize and form functional pores in lipid bilayers.

[1]. R. M. Murphy, Annu. Rev. Biomed. Eng. 2002, 4, 155-174.

[2]. A. Langham, A. Sayyed-Ahmad, Y Kaznessis, Journal of the American Chemical Society, 2008, 130(13): 4338-4346

[3]. H. Jang, B. Ma, R. Nussinov, BMC Structural Biology 2007, 7:21.

[4]. H. Flyvbjerg, H.G. Petersen, J.Chem.Phys. 1989, 91: 461-466.