Two sterols, two bilayers: insights on membrane structure from molecular dynamics

<p>Cholesterol (CHL) and ergosterol (ERG) are two predominant sterols in eukaryotic cells. The differences in their chemical structure can influence membrane structure and dynamics; this study discusses the effect CHL and ERG have on yeast membrane models with characteristic lipid composition for the endoplasmic reticulum (ER) and the trans-Golgi network (TGN) of yeast <i>Saccharomyces cerevisiae</i>. Molecular dynamics simulations were used to understand the atomic details of the sterols’ interaction with lipid bilayers that have both saturated and unsaturated tails as well as neutral and charged headgroups. Our models include phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol lipids to mimic the environment of the ER and TGN. The models for each organelle are identical, respectively, except for the sterol type. The overall surface area per lipid has no statistical difference between models for the same organelle, 63.6 ± 0.4 Å² in the ER and 60.9 ± 0.4 Å² in the TGN with either ERG or CHL. However, the compressibility modulus is approximately 30% lower in the models with ERG. We analyse this difference based on the sterols’ chemical structure and examine other membrane properties such as the lipid tails order parameters, bilayer thicknesses, sterol tilt angles and sterol spatial orientation with respect to the lipid tails to compare trends with existing data from simulation as well as experiment. This is the first study, to our knowledge, to examine the effect of sterol type on multi-lipid bilayer models with all-atom molecular dynamics.</p

Modeling Yeast Organelle Membranes and How Lipid Diversity Influences Bilayer Properties

Membrane lipids are important for the health and proper function of cell membranes. We have improved computational membrane models for specific organelles in yeast <i>Saccharomyces cerevisiae</i> to study the effect of lipid diversity on membrane structure and dynamics. Previous molecular dynamics simulations were performed by Jo et al. [(2009) <i>Biophys J.</i> <i>97</i>, 50–58] on yeast membrane models having six lipid types with compositions averaged between the endoplasmic reticulum (ER) and the plasma membrane (PM). We incorporated ergosterol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol lipids in our models to better describe the unique composition of the PM, ER, and trans-Golgi network (TGN) bilayers of yeast. Our results describe membrane structure based on order parameters (<i>S</i>_CD), electron density profiles (EDPs), and lipid packing. The average surface area per lipid decreased from 63.8 ± 0.4 Ų in the ER to 47.1 ± 0.3 Ų in the PM, while the compressibility modulus (<i>K</i>_A) varied in the opposite direction. The high <i>S</i>_CD values for the PM lipids indicated a more ordered bilayer core, while the corresponding lipids in the ER and TGN models had lower parameters by a factor of at least 0.7. The hydrophobic core thickness (2<i>D</i>_C) as estimated from EDPs is the thickest for PM, which is in agreement with estimates of hydrophobic regions of transmembrane proteins from the Orientation of Proteins in Membranes database. Our results show the importance of lipid diversity and composition on a bilayer’s structural and mechanical properties, which in turn influences interactions with the proteins and membrane-bound molecules

Cooperative Membrane Binding of HIV‑1 Matrix Proteins

The HIV-1 assembly process begins with a newly synthesized Gag polyprotein being targeted to the inner leaflet of the plasma membrane of the infected cells to form immature viral particles. Gag–membrane interactions are mediated through the myristoylated (Myr) N-terminal matrix (MA) domain of Gag, which eventually multimerize on the membrane to form trimers and higher order oligomers. The study of the structure and dynamics of peripheral membrane proteins like MA has been challenging for both experimental and computational studies due to the complex transient dynamics of protein–membrane interactions. Although the roles of anionic phospholipids (PIP2, PS) and the Myr group in the membrane targeting and stable membrane binding of MA are now well-established, the cooperative interactions between the MA monomers and MA-membrane remain elusive in the context of viral assembly and release. Our present study focuses on the membrane binding dynamics of a higher order oligomeric structure of MA protein (a dimer of trimers), which has not been explored before. Employing time-lagged independent component analysis (tICA) to our microsecond-long trajectories, we investigate conformational changes of the matrix protein induced by membrane binding. Interestingly, the Myr switch of an MA monomer correlates with the conformational switch of adjacent monomers in the same trimer. Together, our findings suggest complex protein dynamics during the formation of the immature HIV-1 lattice; while MA trimerization facilitates Myr insertion, MA trimer–trimer interactions in the immature lattice can hinder the same

Dual Action of Hydrotropes at the Water/Oil Interface

Hydrotropes are substances containing small amphiphilic molecules, which increase solubility of nonpolar (hydrophobic) substances in water. Hydrotropes may form dynamic clusters (less or about 1 ns lifetime) with water molecules; such clusters can be viewed as “pre-micelles” or as “micellar-like” structural fluctuations. We present the results of experimental and molecular dynamics (MD) simulation studies of interfacial phenomena and liquid–liquid equilibrium in the mixtures of water and cyclohexane with the addition of a typical nonionic hydrotrope, tertiary butanol. The interfacial tension between the aqueous and oil phases was measured by Wilhelmy plate and spinning drop methods with overlapping conditions in excellent agreement between techniques. The correlation length of the concentration fluctuations, which is proportional to the thickness of the interface near the liquid–liquid critical point, was measured by dynamic light scattering. In addition, we studied the interfacial tension and water–oil interfacial profiles by MD simulations of a model representing this ternary system. Both experimental and simulation studies consistently demonstrate a spectacular crossover between two limits in the behavior of the water–oil interfacial properties upon addition of the hydrotrope: at low concentrations the hydrotrope acts as a surfactant, decreasing the interfacial tension by adsorption of hydrotrope molecules on the interface, while at higher concentrations it acts as a cosolvent with the interfacial tension vanishing in accordance with a scaling power-law upon approach to the liquid–liquid critical point. It is found that the relation between the thickness of the interface and the interfacial tension follows a scaling law in the entire range of interfacial tensions, from a “sharp” interface in the absence of the hydrotrope to a “smooth” interface near the critical point. We also demonstrate the generic nature of the dual behavior of hydrotropes by comparing the studied ternary system with systems containing different hydrocarbons and hydrotropes

Dual Action of Hydrotropes at the Water/Oil Interface

Hydrotropes are substances containing small amphiphilic molecules, which increase solubility of nonpolar (hydrophobic) substances in water. Hydrotropes may form dynamic clusters (less or about 1 ns lifetime) with water molecules; such clusters can be viewed as “pre-micelles” or as “micellar-like” structural fluctuations. We present the results of experimental and molecular dynamics (MD) simulation studies of interfacial phenomena and liquid–liquid equilibrium in the mixtures of water and cyclohexane with the addition of a typical nonionic hydrotrope, tertiary butanol. The interfacial tension between the aqueous and oil phases was measured by Wilhelmy plate and spinning drop methods with overlapping conditions in excellent agreement between techniques. The correlation length of the concentration fluctuations, which is proportional to the thickness of the interface near the liquid–liquid critical point, was measured by dynamic light scattering. In addition, we studied the interfacial tension and water–oil interfacial profiles by MD simulations of a model representing this ternary system. Both experimental and simulation studies consistently demonstrate a spectacular crossover between two limits in the behavior of the water–oil interfacial properties upon addition of the hydrotrope: at low concentrations the hydrotrope acts as a surfactant, decreasing the interfacial tension by adsorption of hydrotrope molecules on the interface, while at higher concentrations it acts as a cosolvent with the interfacial tension vanishing in accordance with a scaling power-law upon approach to the liquid–liquid critical point. It is found that the relation between the thickness of the interface and the interfacial tension follows a scaling law in the entire range of interfacial tensions, from a “sharp” interface in the absence of the hydrotrope to a “smooth” interface near the critical point. We also demonstrate the generic nature of the dual behavior of hydrotropes by comparing the studied ternary system with systems containing different hydrocarbons and hydrotropes