Identifying the Onset of Phase Separation in Quaternary Lipid Bilayer Systems from Coarse-Grained Simulations

Understanding the (de)mixing behavior of multicomponent lipid bilayers is an important step towards unraveling the nature of spatial composition heterogeneities in cellular membranes and their role in biological function. We use coarse-grained molecular dynamics simulations to study the composition phase diagram of a quaternary mixture of phospholipids and cholesterol. This mixture is known to exhibit both uniform and coexisting phases. We compare and combine different statistical measures of membrane structure to identify the onset of phase coexistence in composition space. An important element in our approach is the dependence of composition heterogeneities on the size of the system. While homogeneous phases can be structured and display long correlation lengths, the hallmark behavior of phase coexistence is the scaling of the apparent correlation length with system size. Because the latter cannot be easily varied in simulations, our method instead uses information obtained from observation windows of different sizes to accurately distinguish phase coexistence from structured homogeneous phases. This approach is built on very general physical principles, and will be beneficial to future studies of the phase behavior of multicomponent lipid bilayers

Free Energy Calculations of Membrane Permeation: Challenges due to Strong Headgroup-Solute Interactions

Understanding how different classes of molecules move across biological membranes is a prerequisite to predicting a solute's permeation rate, which is a critical factor in the fields of drug design and pharmacology. We use biased Molecular Dynamics computer simulations to calculate and compare the free energy profiles of translocation of several small molecules across 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayers as a first step towards determining the most efficient method for free energy calculations. We study the translocation of arginine, a sodium ion, alanine, and a single water molecule using the Metadynamics, Umbrella Sampling, and Replica Exchange Umbrella Sampling techniques. Within the fixed lengths of our simulations, we find that all methods produce similar results for charge-neutral permeants, but not for polar or positively charged molecules. We identify the long relaxation timescale of electrostatic interactions between lipid headgroups and the solute to be the principal cause of this difference, and show that this slow process can lead to an erroneous dependence of computed free energy profiles on the initial system configuration. We demonstrate the use of committor analysis to validate the proper sampling of the presumed transition state, which in our simulations is achieved only in replica exchange calculations. Based on these results we provide some useful guidance to perform and evaluate free energy calculations of membrane permeation

Micelle Formation and the Hydrophobic Effect

The tendency of amphiphilic molecules to form micelles in aqueous solution is a consequence of the hydrophobic effect. The fundamental difference between micelle assembly and macroscopic phase separation is the stoichiometric constraint that frustrates the demixing of polar and hydrophobic groups. We present a theory for micelle assembly that combines the account of this constraint with a description of the hydrophobic driving force. The latter arises from the length scale dependence of aqueous solvation. The theoretical predictions for temperature dependence and surfactant chain length dependence of critical micelle concentrations for nonionic surfactants agree favorably with experiment.Comment: Accepted for publication in J. Phys. Chem.