Abstract
We examine the mechanism of formation of micelles of dihydroxy bile salts using a coarse-grained, implicit solvent model and Langevin dynamics simulations. We find that bile salt micelles primarily form via addition and removal of monomers, similarly to surfactants with typical head-tail molecular structures, and not via a two-stage mechanism - involving formation of oligomers and their subsequent aggregation to form larger micelles - originally proposed for bile salts. The free energy barrier to removal of single bile monomers from micelles is ≈2kBT, much less than what has been observed for head-tail surfactants. Such a low barrier may be biologically relevant: it allows for rapid release of bile monomers into the intestine, possibly enabling the coverage of fat droplets by bile salt monomers and subsequent release of micelles containing fats and bile salts - a mechanism that is not possible for ionic head-tail surfactants of similar critical micellar concentrations.
Highlights
Bile salts and bile acids are surfactants that play a key role in the digestion of fats by humans
We demonstrate that our NVT simulations meet this condition by: (i) verifying that the NVT simulations sample the correct micelle size distribution at each concentration by comparison to simulations using grand canonical Langevin dynamics; (ii) confirming that individual molecules sample a wide range of micellar environments by calculating the mean square displacement in micelle size space and comparing its saturation value with predictions from diffusion theory[57]; and (iii) for the most frequent events – the addition and removal of monomers, dimers or trimers to/from micelles, as shown below – by showing that the rates calculated from the micelle size distribution are identical to those directly calculated in the simulation
The coarse-grained model of bile salts used in this work has modest computational cost, enabling the investigation of the mechanisms by which pure bile micelles change aggregation number at concentrations near and far the critical micellar concentration via straightforward Langevin dynamics simulations
Summary
Bile salts and bile acids are surfactants that play a key role in the digestion of fats by humans. The molecular structure of bile salts differs from those of well-studied surfactants like SDS or the DMM component phosphatidylcholine. Instead of the hydrophilic head–hydrophobic tail (head–tail) structure that leads to a prolate shape typically associated with surfactants, bile salts have a rigid steroid group with four rings attached to a short and flexible tail, as shown in Fig. 1(a) for the bile salt taurochenodeoxycholate. The hydrophilic character of one of the steroid faces results from the presence of two or three hydroxyl groups, which are absent from the hydrophobic face. In the upper intestinal tract, the bile salt tail predominantly ends in a hydrophilic glycine or taurine group which, depending on pH, may be charged. Further down in the intestinal tract the taurine or glycine conjugation is removed and the bile salts become more hydrophobic
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