Phase Diagrams Of Lipid Mixtures Research Articles

A machine learning approach to estimation of phase diagrams for three-component lipid mixtures

The plasma membrane of eukaryotic cells is commonly believed to contain ordered lipid domains. The interest in understanding the origin of such domains has led to extensive studies on the phase behavior of mixed lipid systems. Three-component phase diagrams, composed of a high melting temperature (Tm) lipid, cholesterol, and a low Tm lipid have been valuable in studying lipid phase behavior. However, developing phase diagrams over the entire composition space and with precise tie-lines requires significant experimental effort. In this study, a machine learning approach was used to predict the Tm of lipids and generate phase diagrams from lipid mixtures. First, artificial neural network (ANN) was used for the prediction of Tm. The network was trained using available Tm data and was able to generate Tm values that closely matched literature results for its testing dataset. This model was then used to predict the Tm for lipids that have not yet been experimentally tested. Then, random forests (RF) and support vector machines (SVM) were trained and tested for their ability to predict a test three-component phase diagram. The model from the RF algorithm was able to generate a diagram that closely matched published results. This model was then used to generate phase diagrams for lipid mixtures at various temperatures and various degrees of unsaturation. This machine learning approach to the generation of lipid phase diagrams has the potential to save significant time and resources in studies of lipid phase behavior.

Temperature Effect on the Bilayer Stacking in Multilamellar Lipid Vesicles

The small-angle region of the Bragg diffraction of MLV samples is a simple and powerful tool for the study of mesoscopic lipid structures either alone or in interaction with molecules of biological interest. It is also a helpful tool to obtain the much needed thermotropic phase diagrams of lipid mixtures. In the course of our work, we found that the analysis of the diffractograms obtained as a function of temperature is not as straightforward as we expected. When the aqueous medium is concentrated in univalent salts, the small-angle X-ray scattering, SAXS, develops several peaks that have been interpreted to result from regions with different thickness of the interbilayer region. However, a systematic study shows that nonzero ionic strength is by no means a necessary criterion for irregularity of bilayer stacking. We show that MLV in water are uniform and stable if made, kept, and measured at the same temperature. If not, the lamellar repeat distance is smaller than the equilibrated one, eventually developing transient multimodal SAXS diffractions. We present a detailed study of this phenomenon using SAXS and dynamic light scattering and conclude that the deviations from the equilibrium interbilayer distance is a consequence of geometric constraints created by the insufficient thermal expansion of the lipid bilayers.

Simulation of the lo−ld Phase Boundary in DSPC/DOPC/Cholesterol Ternary Mixtures Using Pairwise Interactions

Recently, a number of ternary phase diagrams of lipid mixtures have been constructed using various experimental techniques with a common goal of understanding the nature of lipid domains. An accurate experimental phase diagram can provide rich thermodynamic information and can also be used to extract molecular interactions using computer simulation. In this study, the liquid-ordered and liquid-disordered (l(o)-l(d)) phase boundary of DSPC/DOPC/Cholesterol ternary mixtures is simulated in a lattice model using pairwise interactions. The block composition distribution (BCD) technique was used to locate accurately the compositions of coexisting phases and thermodynamics tie-lines in the two-phase region, and the Binder ratio method was used to determine the phase boundary in the critical region. In simulations performed along a thermodynamic tie-line, the BCD method correctly samples the compositions as well as the relative amounts of coexisting phases, which is in excellent agreement with the lever rule. A "best-fit" phase boundary was obtained that has a top boundary closely resembling the experimental boundary. However, the width of the simulated two-phase region is significantly wider than the experimental one. The results show that pairwise interactions alone are not sufficient to describe the complexity of molecular interactions in the ternary lipid mixtures; more complex forms of interactions, possibly multibody interaction or domain interfacial energy, should be included in the simulation.

Spontaneously Formed Monodisperse Biomimetic Unilamellar Vesicles: The Effect of Charge, Dilution, and Time

Using small-angle neutron scattering and dynamic light scattering, we have constructed partial structural phase diagrams of lipid mixtures composed of the phosphatidylcholines dimyristoyl and dihexanoyl doped with calcium ions (Ca 2+) and/or the negatively charged lipid, dimyristoyl phosphatidylglycerol (DMPG). For dilute solutions (lipid concentration ≤1 wt%), spontaneously forming unilamellar vesicles (ULVs) were found, and their polydispersity was determined to be ∼20%. The stability of the Ca 2+- or DMPG-doped ULVs was monitored over a period of 4 days and their structural parameters (e.g., average outer radius, 〈 R o〉) were found to be insensitive to the lipid concentration ( C lp). However, doping the dimyristoyl/dihexanoyl system with both Ca 2+ and DMPG resulted in ULVs whose 〈 R o〉 was found to be C lp dependent. The 〈 R o〉 of DMPG-doped ULVs remained unchanged over an extended period of time (at least 4 days), a good indication of their stability.

Solid- and liquid-phase equilibria in phosphatidylcholine / phosphatidylethanolamine mixtures. A calorimetric study

Phase diagrams have been determined for mixing of binary mixtures of phosphatidylethanolamines (PE) with phosphatidylcholines (PC), using high-sensitivity differential scanning calorimetry and allowing extensive incubation times to equilibrate samples in the solid phase. All of the PE-PC systems examined, which contained saturated or trans-unsaturated PC components, showed limited solid-phase miscibility, chiefly because the PC component can adopt more solid phases than the PE component. For the dielaidoyl PE-PC system, the lamellar-to-hexagonal II transition endotherm seen at 63.5°C for the pure PE is shifted to considerably higher temperatures upon incorporation of even low mode fractions of PC. All of the PE-PC systems examined here reveal a complete miscibility in the liquid phase, including the dipalmitoyl PE-dielaidoyl PC system for which limited liquid-phase miscibility had previously been suggested (Wu, S-H. and McConnell, H.M. (1975) Biochemistry 14, 847–854). However, PE-PC mixing appears to be less nearly ideal than the mixing of either PE or PC with anionic phospholipids. Our results demonstrate that calorimetry can be useful in determining accurate phase diagrams for lipid mixtures of this type, but only if proper attention is given to the existence and the proper equilibration of multiple solid phases in these systems.