Spontaneous self-aggregation of bilirubin in water induced by non-covalent forces.

Unconjugated bilirubin (UCB) accumulation in the blood causes several diseases, such as jaundice, and most studies in the literature focus on settling these problems. However, its yellow-orange colour, antioxidant and anti-inflammatory activities and other properties have stimulated recent research to investigate this natural pigment for medical applications. Despite its polar groups, bilirubin is insoluble in water. Herein, we discuss the self-aggregation of UCB in water to understand its collective interactions employing molecular dynamics simulations. Starting from a random distribution of UCB molecules, we observed small clusters forming in a short simulation time. After that, they merged to form a single spherical aggregate. We attributed this behaviour to the preferential interactions between acid and basic groups of UCB through intermolecular and intramolecular hydrogen bonds. The electrostatic contribution between UCBs in aggregate is 150 kJ ⋅ mol − 1 , smaller than the UCB dispersed in water. Consequently, the contact between water and UCB was three times lower. Furthermore, we found that the central methylenes that bind the UCB dipyrrinones moieties are distributed in the nanoaggregate, like regular concentric layers, with a radius of 0.42 nm. • The central methylenes of bilirubin are distributed in the aggregates as if they were in concentric layers 0.42 nm apart. • Due to the non-covalent interaction forces between bilirubin, the H-bonds between bilirubin and water are unfavourable. • The self-aggregation of bilirubin in water produces a spherical-shaped material with no water in its interior. [ABSTRACT FROM AUTHOR]