Molecular Dynamics Simulation of the Aggregation Patterns in Aqueous Solutions of Bile Salts at Physiological Conditions

Abstract

Classical molecular dynamics simulations are employed to monitor the aggregation behavior of six bile salts (nonconjugated and glycine- and taurine-conjugated sodium cholate and sodium deoxycholate) with concentration of 10 mM in aqueous solution in the presence of 120 mM NaCl. There are 150 ns trajectories generated to characterize the systems. The largest stable aggregates are analyzed to determine their shape, size, and stabilizing forces. It is found that the aggregation is a hierarchical process and that its kinetics depends both on the number of hydroxyl groups in the steroid part of the molecules and on the type of conjugation. The micelles of all salts are similar in shape-deformed spheres or ellipsoids, which are stabilized by hydrophobic forces, acting between the steroid rings. The differences in the aggregation kinetics of the various conjugates are rationalized by the affinity for hydrogen bond formation for the glycine-modified salts or by the longer time needed to achieve optimum packing for the tauro derivatives. Evidence is provided for the hypothesis from the literature that the entirely hydrophobic core of all aggregates and the enhanced dynamics of the molecules therein should be among the prerequisites for their pronounced solubilization capacity for hydrophobic substances in vivo.

Probing the molecular interactions between pharmaceutical polymeric carriers and bile salts in simulated gastrointestinal fluids using NMR spectroscopy

“…[28][29][30] A few research groups have described the aggregation pattern of NaTC being a "progressive process", even at very low concentrations, rather than a sharp transition of aggregation behavior at a critical concentration point. [15,31,32] The presence of excipients in the formulations used for delivering the poorly soluble drugs may affect the aggregation behavior of the bile salts and their solubilisation functions. The present work focuses on investigating the intermolecular interplay occurring between most commonly pharmaceutical polymers used in solid dispersion based formulations and bile salts as representatives of the biosurfactants present in the gastro-intestinal media.…”

Importance of Conjugation of the Bile Salt on the Mechanism of Lipolysis

“…The hydrogen bonds between these groups result in added induced dipole interactions of the hydrophobic sections. This has been shown by molecular dynamics simulations [40,41]. Conjugated BS offers additional sites for H-bond formation, especially between the peptide amino group and the steroid hydroxyl groups.…”

“…Table 3. The number of BS-BS hydrogen bonds and number of BS-water hydrogen bonds of four groups of BS [41]. Secondary unconjugated BS could be characterized by the smallest number of BS-BS HBs and number of BS-water HBs, while the primary conjugated has the highest number of BS-water HBs.…”

Study on Micelle Formation of Bile Salt Using Nuclear Magnetic Resonance Spectroscopy

“…The remarkably differences in T 1 for each bile salt molecule are only shown for the difference structure of micelle on NaTC. The argument for the contribution of hydrogen bonding with including number and position using molecular dynamics simulations still continues even today 29 . In order to clarify the mechanism of bile salt micelle formation, it will be necessary to reconcile the results of computer simulations and experiment studies.…”