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Interaction of Bile Salts With Lipid Bilayers: An Atomistic Molecular Dynamics Study.

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.

SUBMITTER: Neves MC

PROVIDER: S-EPMC6465969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human β defensin type 3 (hBD-3) is a small cationic cysteine-rich peptide. It has a broad spectrum of antimicrobial activities. However, at high concentrations, it also shows hemolytic activity by interrupting red blood cells. To understand the selectivity of hBD-3 disrupting cell membranes, investigating the capability of hBD-3 translocating through different membranes is important. Since hBD-3 in the analogue form in which all three pairs of disulfide bonds are broken has similar antibacterial activities to the wild-type, this project investigates the structure and dynamics of an hBD-3 analogue in monomer, dimer, and tetramer forms through both zwitterionic and negatively charged lipid bilayers using molecular dynamics (MD) simulations. One tetramer structure of hBD-3 was predicted by running all-atom MD simulations on hBD-3 in water at a high concentration, which was found to be stable in water during 400 ns all-atom simulations based on root-mean-squared deviation, root-mean-squared fluctuation, buried surface area, and binding interaction energy calculations. After that, hBD-3 in different forms was placed inside different membranes, and then steered MD simulation was conducted to pull the hBD-3 out of the membrane along the z-direction to generate different configurational windows to set up umbrella-sampling (US) simulations. Because extensive sampling is important to obtain accurate free energy barriers, coarse-grained US MD simulations were performed in each window. Based on the long-term simulation result, membrane thinning was found near hBD-3 in different lipid bilayers and in different hBD-3 oligomer systems. By calculating the root-mean-squared deviation of the z-coordinate of hBD-3 molecules, rotation of the oligomer inside the bilayer and stretching of the oligomer structure along the z-direction were observed. Although reorientation of lipid heads toward the hBD-3 tetramer was observed based on the density profile calculation, the order parameter calculation shows that hBD-3 disrupts 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) lipids more significantly and makes it less ordered than on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Calculating the free energy of hBD-3 through different lipid bilayers, it was found that generally hBD-3 encounters a lower energy barrier through negatively charged lipid membranes than the zwitterionic membrane. hBD-3 in different forms needs to overcome a lower energy barrier crossing the combined POPC+POPS bilayer through the POPS leaflet than through the POPC leaflet. Besides that, the potential of mean force result suggests that hBD-3 forms an oligomer translocating negatively charged lipid membranes at a low concentration. This study supplied new insight into the antibacterial mechanism of hBD-3 through different membranes.

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Interaction of Bile Salts With Lipid Bilayers: An Atomistic Molecular Dynamics Study.

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