Structure and Dynamics of Cholic Acid and Dodecylphosphocholine−Cholic Acid Aggregates

Abstract

Bile acids are powerful detergents that emulsify and solubilize lipids, vitamins, cholesterol and other molecules in the biliary tract and intestines. It has long been known that bile acids form soluble mixed micelles with lipids. However, the detailed thermodynamic and structural properties of these micelles are not fully understood. This study sheds light on this issue based on results from multiple molecular dynamics simulations of cholic acid (CA) and dodecylphosphocholine (DPC) mixed micelles. We found that CA molecules form aggregates of up to 12 monomers with a mean size of 5–6. In agreement with several previous simulations and earlier predictions, the overall shape of these CA clusters is oblate disk-like such that the methyl groups point toward the core of the aggregate and the hydroxyl groups point away from it. The self-aggregation behavior of the CA clusters in the DPC-CA mixture is similar to the pure CA. Furthermore, the sizes and aggregation numbers of the DPC-CA mixed micelles are linearly dependent on CA molarity. In agreement with the radial shell model of Nichols and Ozarowski [Nichols, J. W.; Ozarowski, J. Biochemistry 1990, 29, 4600]1, our results demonstrate that CA molecules form a wedge between the DPC molecules with their hydroxyl and carboxyl groups facing the aqueous phase while their methyl groups are buried in and face the hydrocarbon core of the DPC micelle. The DPC-CA micelles simulated here tend to be spherical to prolate in shape, with the deviation from spherical geometry significantly increasing with increasing CA:DPC ratio.

Aggregation behavior of ibuprofen, cholic acid and dodecylphosphocholine micelles

“…Subsequent studies [42,43] found features of a disk-shaped micelle originally proposed by Carey and Small [44]. Our own previous study on pure cholic acid (CA) and CA-dodecylphosphocholine (DPC) micelles supported the radial-shell model and revealed a linear dependence of micelle size on CA concentration [45]. …”

“…The stability of the simulations was monitored by the time evolution of the number of CA or IBU monomers (N Monomers ), as well as the weight and number averaged aggregation numbers N W and N N (Figure S3). N W and N N , as well as principal moments of inertia I 1 , I 2 and I 3 , were calculated as described before [45]. The weighted probability distribution (P n ) of micelles and monomers was calculated as: $$P_n=\frac{X}{N}\text{ where }X=\frac{\left({\displaystyle \sum _{F=1}^{N_F}}\mathit{\text{nCSn}}\right)}{N_F}.$$ CSn is the number of CA-IBU mixed-micelles of size n ( n =2, 3, 4…) or the number of CA and IBU monomers ( n = 1), F is frame index, N F is the total number of frames sampled every 10ps and N the total number of CA and IBU molecules in the system.…”

“…The starting configurations for CA and IBU were built based on the CHARMM general force field (CGenFF) [47]. The initial structure for the ternary mixture was built by randomly adding IBU molecules onto the last snapshot of a previously reported simulation of CA adsorbed on a DPC micelle [45]. Each system was then energy minimized with the steepest descent method for 100,000 steps and equilibrated as described previously [45].…”

“…The initial structure for the ternary mixture was built by randomly adding IBU molecules onto the last snapshot of a previously reported simulation of CA adsorbed on a DPC micelle [45]. Each system was then energy minimized with the steepest descent method for 100,000 steps and equilibrated as described previously [45]. All simulations were performed with the NAMD program [48] at 310K and 1atm.…”

Water confined in self-assembled ionic surfactant nano-structures

“…Molecular dynamics simulations at the mesoscale are the most indicated tool to address the issues discussed in the main text. It is interesting to note that only limited surfactants phase diagram regions have been generally considered in the literature, focusing particularly on micellar phases [30][31][32][33] , in high hydration conditions. These works mostly report phase diagrams and basic structural details, in the form of pair distribution functions and typical sizes of surfactant clusters.…”