STUDY OF THE MICELLE FORMATION PROCESS OF BILE ACIDS THROUGHMOLECULAR DYAMICS SIMULATIONS

A series of recent discoveries has expanded the role of bile acids (BAs) beyond their well-established function as endogenous detergents of the body [1]. Consistent with their pleiotropic action in vivo, BAs are indeed ligands for the nuclear farnesoid X receptor (FXR) and for the G-protein-coupled receptor TGR5/Gpbar1, as well as are able to activate the pregnane X receptor (PXR), constitutive androstane receptor (CAR) and vitamin D receptor (VDR). Through the modulation of these diverse signalling pathways, BAs have shown to control not only their own homeostasis but also fat glucose and energy metabolism [2].Thus, in the design and development of new BA-based compounds, the physicochemical profile of the molecules must be timely explored and analyzed. Diverse BA-modified derivatives exhibit different physico-chemical properties and even more divergent biological characteristic [3]. In this scenario, the critical micellar concentration (CMC) of the relative bile salts (BSs) is particularly noteworthy.Primary micelles are formed by 2-10 monomers and their formation is driven by hydrophobic association of β-faces of single monomers.Secondary micelles are formed by 10-100 monomers and materialize through hydrogen bonding of primary micelles involving also the α-face of bile acids. With the aim to study the effect on the micelles formation of the substitutions on position 6, 12 and 23 of the steroidal scaffold, a molecular dynamics approach has been applied. Eight species have been studied: Cholic Acid, Chenodeoxycholic Acid, 6α-Ethyl-cholic Acid, 6α-Ethyl-chenodeoxycholic Acid, 23(R)-methyl-cholic Acid , 23(S)-methyl-cholic Acid , 6α-Ethyl-23(R)-methyl-cholic Acid and 6α-Ethyl-23(S)-methyl-cholic Acid. In particular we tried to identify how the presence of the 6-ethyl, the 23-methyl and the 12-OH could influence this process.