Simulation Studies On Organelle-Specific Yeast Membrane Models and Amphipathic Lipid Packing Sensor (ALPS) Motif Binding Mechanism

This research presents improved computational membrane models for specific organelles in yeast. Previous molecular dynamic (MD) simulations were performed on yeast membrane models having six lipid types with lipid composition averages between the endoplasmic reticulum (ER) and the plasma membrane (PM).[i] Present models include ergosterol (ERG), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI) lipids, with bilayer diversity ranging between six and eleven lipid types with varying degrees of chain unsaturation. MD simulations were used to equilibrate systems with lipid compositions characteristic to the ER, PM, and trans-Golgi network (TGN) membranes. Data analysis provided a better understanding of membrane behavior, e.g., mechanical properties, deuterium order parameters, electron density profiles, and lipid packing. Selected models will be used to advance the study of the binding mechanism and function of a yeast peripheral membrane protein, Osh4. Drin et al suggested the ALPS-like motif in Osh4 interacts with the membrane bilayer and facilitate sterols transport.[ii] Our interest in this peptide comes from previous results from our lab that showed it is involved in membrane binding.[iii]ALPS-like motif binding mechanism to DOPC and DPPC bilayers was studied with MD simulations of at least 100ns. MD simulations in the constant surface tension ensemble will directly investigate the effect of lipid packing to ALPS binding.  Then, bilayer diversity will be increased to study the effects of lipid packing and degree of unsaturation to the peptide’s binding mechanism.

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[i] Jo, S.; Lim, J.B.; Klauda, J.B.; Im, W. CHARMM-GUI Membrane Builder for Mixed Bilayers and Its Application to Yeast Membranes.  Biophys. J. (2009) 97, 50-58.

[ii] Drin, G. Casella, J.; Gautier, R.; Boehmer, T.; Schwartz, T.U.; Antonny, B. A general amphipathic α-helical motif for sensing membrane curvature. Nat. Struc. Mol. Biol. (2007) 14:2, 138-146.

[iii] Rogaski, B.; Klauda, J.B. Membrane-Binding Mechanism of a Peripheral Membrane Protein through Microsecond Molecular Dynamics Simulations.  J. Mol. Biol. (2012) 423, 847-862.

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