Molecular dynamics simulations of hydrotropic solubilization and self-aggregation of nicotinamide.

Hydrotropy is a phenomenon where the presence of a large quantity of one solute enhances the solubility of another solute. The mechanism of this phenomenon remains elusive and a topic of debate. This study employed molecular dynamics simulation to investigate the hydrotropic mechanism of a model system consisting of a hydrotropic agent, nicotinamide (NA), a poorly water-soluble solute, PG-300995 (PG), and water. Our study demonstrates that NA and PG undergo significant aggregation in the aqueous solution, a result correlating closely to the self-aggregation of NA under the same conditions. The correlations are found both structurally and dynamically, suggesting that the self-aggregation of NA may be a prerequisite, or at least a major contributor, to its hydrotropic effects. The self-aggregation of NA allows the segregation of the hydrophobic solute from water, a key step to ease the energy increase to the system. Energetic evidences directly show that the hydrotropic solubilization is favored in the presence of NA aggregation. These results are in strong support of the molecular aggregation hypothesis for hydrotropic solubilization. Additionally, it is found that the restoration of water-water HBs from the interference of the NA and PG molecules plays an important role for the aggregation. The HBs between the solute and the hydrotrope may contribute, but is not vital, to the aggregation and hence the hydrotropic effects. The dynamic data confirm that the aggregates, while remain in liquid state, are much more active dynamically than a pure NA amorphous/liquid phase under the same temperature and pressure. By equilibrating an NA amorphous agglomerate with water, it is found that the aggregation state, rather than an NA-water two phase system, is the equilibrium state of the NA + water system.

Silica xerogel/aerogel-supported lipid bilayers: consequences of surface corrugation.

The objective of this paper was to review our recent investigations of silica xerogel and aerogel-supported lipid bilayers. These systems provide a format to observe relationships between substrate curvature and supported lipid bilayer formation, lipid dynamics, and lipid mixtures phase behavior and partitioning. Sensitive surface techniques such as quartz crystal microbalance and atomic force microscopy are readily applied to these systems. To inform current and future investigations, we review the experimental literature involving the impact of curvature on lipid dynamics, lipid and phase-separated lipid domain localization, and membrane-substrate conformations and we review our molecular dynamics simulations of supported lipid bilayers with the atomistic and molecular information they provide.

Density imbalances and free energy of lipid transfer in supported lipid bilayers.

Supported lipid bilayers are an abundant research platform for understanding the behavior of real cell membranes as they allow for additional mechanical stability and at the same time have a fundamental structure approximating cell membranes. However, in computer simulations these systems have been studied only rarely up to now. An important property, which cannot be easily determined by molecular dynamics or experiments, is the unsymmetrical density profiles of bilayer leaflets (density imbalance) inflicted on the membrane by the support. This imbalance in the leaflets composition has consequences for membrane structure and phase behavior, and therefore we need to understand it in detail. The free energy can be used to determine the equilibrium structure of a given system. We employ an umbrella sampling approach to obtain the free energy of a lipid crossing the membrane (i.e., lipid flip-flop) as a function of bilayer composition and hence the equilibrium composition of the supported bilayers. In this paper, we use a variant of the coarse-grained Martini model. The results of the free energy calculation lead to a 5% higher density in the proximal leaflet. Recent data obtained by large scale modeling using a water free model suggested that the proximal leaflet had 3.2% more lipids than the distal leaflet [Hoopes et al., J. Chem. Phys. 129, 175102 (2008)]. Our findings are in line with these results. We compare results of the free energy of transport obtained by pulling the lipid across the membrane in different ways. There are small quantitative differences, but the overall picture is consistent. We additionally characterize the intermediate states, which determine the barrier height and therefore the rate of translocation. Calculations on unsupported bilayers are used to validate the approach and to determine the barrier to flip-flop in a free membrane.

Coarse-grained modeling of lipids.

Molecular modeling of phospholipids on many scales has progressed significantly over the last years. Here we review several membrane models on intermediate to large length scales restricting ourselves to particle based coarse-grained models with implicit and explicit solvent. We explain similarities and differences as well as their connection to experiments and fine-grained models. We neglect any field descriptions on larger scales. We discuss then a few examples where we focus on studies of lipid phase behavior as well as supported lipid bilayers as these examples can only be meaningfully studied using large-scale models to date.

Interactions of lipid bilayers with supports: a coarse-grained molecular simulation study.

The study of lipid structure and phase behavior at the nanoscale is of utmost importance due to implications in understanding the role of the lipids in biochemical membrane processes. Supported lipid bilayers play a key role in understanding real biological systems, but they are vastly underrepresented in computational studies. In this paper, we discuss molecular dynamics simulations of supported lipid bilayers using a coarse-grained model. We first focus on the technical implications of modeling solid supports for biomembrane simulations. We then describe noticeable influences of the support on the systems. We are able to demonstrate that the bilayer system behavior changes when supported by a hydrophilic surface. We find that the thickness of the water layer between the support and the bilayer (the inner-water region in the latter part of this paper) adapts through water permeation on the microsecond time scale. Additionally, we discuss how different surface topologies affect the bilayer. Finally, we point out the differences between the two leaflets induced by the support.

Simulations of Biomembranes and Water: Important Technical Aspects.

In this contribution, we discuss several important technical aspects which are relevant for the molecular modeling of biomembranes in aqueous environments. We study the effect of coarse-grained water models on free and supported systems and show that the choice of water model has dramatic repercussions on the phase behavior. We characterize the phase behavior of a widely used water model and discuss the technical implications of modeling solid supports for biomembrane simulations. Finally, we compare the effect of anisotropic pressure coupling with surface tension coupling in atomistic bilayer simulations including alcohols.

On the calculation of time correlation functions by potential scaling.

We present and analyze a general method to calculate time correlation functions from molecular dynamics on scaled potentials for complex systems for which simulation is affected by broken ergodicity. Depending on the value of the scaling factor, correlations can be calculated for times that can be orders of magnitude longer than those accessible to direct simulations. We show that the exact value of the time correlation functions of the original system (i.e., with unscaled potential) can be obtained, in principle, using an action-reweighting scheme based on a stochastic path-integral formalism. Two tests (involving a bistable potential model and a dipeptide bond-vector orientational relaxation) are exemplified to showcase the strengths, as well as the limitations of the approach, and a procedure for the estimation of the time-dependent standard deviation error is outlined.