The effect of bilirubin on Bad, Bak, and Bim pro-apoptotic factors: A molecular dynamic simulation study

Abstract

Bilirubin, an endogenous catabolic product of the heme catabolism, can induce apoptosis in damaged cells. This study investigated the effect of bilirubin on three pro-apoptotic factors Bad, Bak, and Bim using docking and molecular dynamics simulation. Three-dimensional structures were obtained from PubChem and RCSB servers. The simulation was accomplished at 40 nanoseconds (ns) using GROMACS 2018 simulation package before docking. Then bilirubin, as a ligand, bound to these proteins by Autodock v.4.2.6 software, and molecular dynamics simulation were performed again. The hydrophobic and hydrogen bonds at the binding site were determined using LigPlot+V.4.5.3 software. Our study revealed that bilirubin has the highest tendency to bind the Bim. This binding occurred between the 10 residues at the Bim binding site with the lowest binding energy (-8.43 kcal/mol). The docking of bilirubin to Bad, Bak, and Bim decreased Total Energy (TE), increased Radius of gyration (Rg), and root-mean-square deviation (RMSD). The coil secondary structures of Bad and Bim increased significantly after docking the bilirubin. Due to exhibiting a high tendency to interact with Bad, Bak, and Bim, bilirubin can affect their molecular dynamics and increase their activity so that, apoptosis is induced in the cell, which is considered in cancer treatment.