Understanding pharmacokinetic food effects using molecular dynamics simulation coupled with physiologically based pharmacokinetic modeling.

In this study, a molecular dynamics (MD) method is assessed as a new front-end tool for deriving relevant drug-micelle partitioning rates for use in conjunction with a compartmental-style gastrointestinal absorption model. A refined mechanistic approach for handling micelle-associated vs unbound drug is presented and examined in terms of its utility for projecting human oral pharmacokinetic food/formulation effects. Similar to predecessor oral absorption models, the intestinal drug absorption rate is formulated as a function of the combined permeability through the unstirred water layer and the epithelial membrane, however, an additional diffusion coefficient adjustment is applied to account for the viscosity changes of the postprandial small intestine.

Hydrophobic mismatch and lipid sorting near OmpA in mixed bilayers: atomistic and coarse-grained simulations.

To understand the effects of lipid composition on membrane protein function in a mixture as complex as a biomembrane, one must know whether the lipid composition local to the protein differs from the mean lipid composition. In this study, we simulated the transmembrane domain of a β-barrel protein, OmpA, in mixtures of lipids of different tail lengths under conditions of negative hydrophobic mismatch, i.e.

Atomistic simulation of cholesterol effects on miscibility of saturated and unsaturated phospholipids: implications for liquid-ordered/liquid-disordered phase coexistence.

Mixed MD/MC simulation at fixed difference in chemical potential (Δμ) between two lipid types provides a computational indicator of the relative affinities of the two lipids for different environments. Applying this technique to ternary DPPC/DOPC/cholesterol bilayers yields a DPPC/DOPC ratio that increases with increasing cholesterol content at fixed Δμ, consistent with the known enrichment of DPPC and cholesterol-rich in liquid-ordered phase domains in the fluid-fluid coexistence region of the ternary phase diagram. Comparison of the cholesterol-dependence of PC compositions at constant Δμ with experimentally measured coexistence tie line end point compositions affords a direct test of the faithfulness of the atomistic model to experimental phase behavior.

Atomistic simulation of hydrophobic matching effects on lipid composition near a helical peptide embedded in mixed-lipid bilayers.

The local lipid composition near a transmembrane helical peptide in mixed-lipid bilayers has been studied using a mixed molecular dynamics (MD) and configuration-bias Monte Carlo method that allows the lateral distribution of lipids to equilibrate much more quickly than is possible by diffusive mixing alone. Gramicidin-A peptide was embedded in bilayer mixtures of DMPC with either DDPC (shorter by four carbons per tail) or DSPC (longer by four carbons per tail) at 330 K to investigate the possibility of lipid sorting by tail length. Conventional MD simulations showed local thickening of the bilayer near the peptide in pure DDPC and local thinning of the bilayer in pure DSPC, with comparatively little perturbation to the thickness of pure DMPC bilayers, suggesting that DMPC has the best matched tail length to the peptide of these three.

Molecular dynamics simulations of glycocholate-oleic acid mixed micelle assembly.

We have applied a molecular dynamics (MD) method to investigate the aggregation behavior and physicochemical properties of bile salt as well as bile salt/fatty acid mixed micelles. Local atomic density profiles from the center of the micelles confirm that the self-assembly of the trihydroxy bile salt, glycocholate, is largely driven by hydrophobic aggregation of the nonpolar beta-faces of the steroid backbones. Additional association occurs between neighboring monomers through hydrogen-bonding interactions.

Bilayer edge and curvature effects on partitioning of lipids by tail length: atomistic simulations.

The partitioning of lipids among different microenvironments in a bilayer is of considerable relevance to characterization of composition variations in biomembranes. Atomistic simulation has been ill-suited to model equilibrated lipid mixtures because the time required for diffusive exchange of lipids among microenvironments exceeds typical submicrosecond molecular dynamics trajectories. A method to facilitate local composition fluctuations, using Monte Carlo mutations to change lipid structures within the semigrand-canonical ensemble (at a fixed difference in component chemical potentials, Deltamu), was recently implemented to address this challenge.

Equilibrium distributions of dipalmitoyl phosphatidylcholine and dilauroyl phosphatidylcholine in a mixed lipid bilayer: atomistic semigrand canonical ensemble simulations.

Conventional molecular dynamics (MD) simulations are seriously limited by the slow rate of diffusive mixing in their ability to predict lateral distributions of different lipid types within mixed-lipid bilayers using atomistic models. A method to overcome this limitation, using configuration-bias Monte Carlo (MC) "mutation" moves to transform lipids from one type to another in dynamic equilibrium, is demonstrated in binary fluid-phase mixtures of lipids whose tails differ in length by four carbons. The hybrid MC-MD method operates within a semigrand canonical ensemble, so that an equilibrium composition of the mixture is determined by a constant difference in chemical potential (Delta(mu)) chosen for the components.