Molecular Dynamics Simulations Of Dna Pol Beta Phosphorylation-Induced Structural Changes

DNA polymerase β is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a dRP Lyase activity. The atomic structure for the enzyme has recently been elucidated. DNA polymerase β was shown to be phosphorylated in vitro with Protein Kinase C at serines 44 and 55, resulting in loss of its polymerase enzymic activity, but not its ability to bind ss DNA (Tokai et al, J Biol Chem. 1991;266(17):10820-4.). In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase β using molecular dynamic simulations. Different systems were simulated with the following types of phosphorylations; serine 44, serine 55, and serine 44 and 55 together. The simulations show DNA polymerase β structure was subjected to highest structural deviations (RMSD) and fluctuations (RMSF) with serine 44 phosphorylation. In addition, the structure becomes more swollen as evidenced by higher radius of gyration (Rg) values. Cluster analysis of structures was also performed and confirmed the stronger effect of phosphorylation at serine 44. The results suggest that the phosphorylation of serine 44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.