Distinctive Weak Interactions Underlie Diverse Nucleation and Small-Angle Scattering Behavior of Aqueous Cholesterol, Cholesteryl Hemisuccinate, and Glycocholic Acid

Increased total cholesterol is a major cause of serious heart ailments leading to an estimated 3 million deaths annually throughout the world. Understanding the flocculation behavior of small lipids is thus quintessential. Nucleation, small-angle scattering, and dynamical behavior of lipids and analogues like cholesterol (CHL), cholesteryl hemisuccinate (CHM), and glycocholic acid (GHL) are studied in water by molecular dynamics simulation. The study shows a distinct aggregation behavior of these physiologically relevant molecules owing to a systematic gradation in their non-bonding interactions with solvents and near neighbors. Spontaneous self-assemblies formed during simulation are observed to have different stability, aggregation patterns, and dynamics depending crucially on the nature of the hydrophobic/hydrophilic tails. With increasing hydrophilicity, in the order CHL < CHM < GHL, the aggregates become breakable and less compact, often interposed by water molecules in the interstitial spaces between the lipids. Small-angle scattering data obtained from our simulations provide insights toward the structural integrity and shape of the aggregates formed. Unique features are noticed while following the time evolution of the packing of the nucleated assemblies from the solution phase in terms of local density and molecular orientation. As hydrophilicity increases from CHL to GHL, the packing becomes progressively erratic with diverse angles between the molecular vectors. Surface electrostatic potential calculation indicates drastic increase in positive surface charge from CHL to CHM, which has strong implication in water and ion transport through membranes. These observations can be further correlated to comprehend the flocculation of cholesterol and bile acids in the human body.