Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.11889/8501
Title: Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
Authors: Homouz, Dirar 
ShahirShamsir, Mohd 
Moustafa, Ibrahim M. 
Idriss, Haitham T. 
Keywords: Molecular dynamics - Simulations;Supramolecular electrochemistry;Electrostatics;Serine phosphorylation;DNA polymerases;DNA polymerase b activity
Issue Date: 2018
Publisher: Journal of Molecular Graphics and Modelling
Abstract: DNA polymerase b 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 deoxyribose phosphate (dRP) lyase activity. DNA polymerase b was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase b using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.
URI: http://hdl.handle.net/20.500.11889/8501
DOI: 10.1016/j.jmgm.2018.08.007
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