Abstract
Bile salts (BS) are biosurfactants crucial for emulsification and intestinal absorption of cholesterol and other hydrophobic compounds such as vitamins and fatty acids. Interaction of BS with lipid bilayers is important for understanding their effects on membranes properties. The latter have relevance in passive diffusion processes through intestinal epithelium such as reabsorption of BS, as well as their degree of toxicity to intestinal flora and their potential applications in drug delivery. In this work, we used molecular dynamics simulations to address at the atomic scale the interactions of cholate, deoxycholate, and chenodeoxycholate, as well as their glycine conjugates with POPC bilayers. In this set of BS, variation of three structural aspects was addressed, namely conjugation with glycine, number and position of hydroxyl substituents, and ionization state. From atomistic simulations, the location and orientation of BS inside the bilayer, and their specific interactions with water and host lipid, such as hydrogen bonding and ion-pair formation, were studied in detail. Membrane properties were also investigated to obtain information on the degree of perturbation induced by the different BS. The results are described and related to a recent experimental study (Coreta-Gomes et al., 2015). Differences in macroscopic membrane partition thermodynamics and translocation kinetics are rationalized in terms of the distinct structures and atomic-scale behavior of the bile salt species. In particular, the faster translocation of cholate is explained by its higher degree of local membrane perturbation. On the other hand, the relatively high partition of the polar glycine conjugates is related to the longer and more flexible side chain, which allows simultaneous efficient solvation of the ionized carboxylate and deep insertion of the ring system.
Highlights
Bile salts (BS) are amphiphilic molecules synthesized in the liver and secreted into the intestinal lumen, that are involved in several biological functions such as, emulsification of hydrophobic compounds (Monte et al, 2009), signaling, metabolic and inflammatory regulation (Hylemon et al, 2009); and antibacterial activity (Urdaneta and Casadesús, 2017)
Primary BS are synthesized from cholesterol in hepatocytes, in a complex sequence of enzymatic reactions that lead to oxidation of cholesterol aliphatic side-chain to a carboxylic group and addition of hydroxyl groups to the ring system (Russell, 2003)
We report atomistic MD simulations of CA, CDCA, and DCA BS molecules, both in their ionized and non-dissociated species, as well as the ionized form of their glycine conjugates (GCA, GCDCA, and GDCA), interacting with a 1-palmitoyl-2-oleoyl-sn-glycero-3phosphocholine (POPC) bilayer
Summary
Bile salts (BS) are amphiphilic molecules synthesized in the liver and secreted into the intestinal lumen, that are involved in several biological functions such as, emulsification of hydrophobic compounds (Monte et al, 2009), signaling, metabolic and inflammatory regulation (Hylemon et al, 2009); and antibacterial activity (Urdaneta and Casadesús, 2017). We report atomistic MD simulations of CA, CDCA, and DCA BS molecules, both in their ionized (basic) and non-dissociated (acid, here designated as CAH, CDCAH, and DCAH, respectively) species, as well as the ionized form of their glycine conjugates (GCA, GCDCA, and GDCA), interacting with a 1-palmitoyl-2-oleoyl-sn-glycero-3phosphocholine (POPC) bilayer (see Figure 1 for structures and numbering of relevant atoms) Both ionization states were considered for the unconjugated BS, because even though the basic species are expected to be dominant in aqueous media [pKa between 4.5 and 5.1 at 25◦C (Moroi et al, 1992)], the substantially more lipophilic protonated forms interacts preferably with lipid bilayers leading to an increase in the apparent pKa with the protonated form being significant even at neutral pH (CoretaGomes et al, 2015). Simulations were done at a relatively low BS/POPC molecular ratio (2:128), allowing to characterize and distinguish the interaction between the BS and the membrane based on their different molecular structures
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